Orofacial Disorders: Editors

João N. A.
R Ferreira
James Fricton
Nelson Rhodus
Editors
Orofacial Disorders
Current Therapies
in Orofacial Pain and
Oral Medicine
123
Orofacial Disorders
João N.A.R. Ferreira • James Fricton
Nelson Rhodus
Editors
Orofacial Disorders
Current Therapies in Orofacial Pain and
Oral Medicine
Editors
João N.A.R. Ferreira Nelson Rhodus
Faculty of Dentistry Diagnostic and Surgical Sciences
National University of Singapore University of Minnesota
Singapore Minneapolis, MN, USA
James Fricton
Diagnostic and Surgical Sciences
University of Minnesota
Edina, MN, USA
ISBN 978-3-319-51507-6 ISBN 978-3-319-51508-3 (eBook)

DOI 10.1007/978-3-319-51508-3
Library of Congress Control Number: 2017943711
© Springer International Publishing AG 2017

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To our families,
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Preface
Orofacial disorders are common in the general population causing chewing dys-
function, dental pain, intraoral pain, facial pain, jaw pain, earaches, and/or head-
ache. Orofacial disorders including oral cancer and lesions, oral candidiasis, salivary
gland dysfunctions, temporomandibular disorders, occlusal dysfunction and dyses-
thesia, orofacial pain disorders, oral neurosensory disturbances, malodor, orofacial
dystonias and dyskinesias, burning mouth syndrome, oral parafunctions, sleep
apnea and snoring disturbances, and others are very common in all dental and medi-
cal practices with a collective prevalence of over 40% of the population. Management
of these disorders differs from traditional dental practice because the dentist spends
significant clinic time providing medically based evaluation and treatment for these
patients. Services are usually reimbursed by time for consultation and procedures
through the patient’s medical insurance plans similar to physicians.
This guide is a quick reference for practicing clinicians. Its purpose is to provide
a concise evidence-based clinical summary of diagnosis, etiology, and management
of the most common orofacial disorders. Each chapter includes succinct bullet
points, tables, and illustrations that summarize important points in understanding
each orofacial disorder. In addition, interdisciplinary and multidisciplinary orofa-
cial pain management recommendations are presented to improve effectiveness
while providing patient care. Integrative therapies for pain management such as
biofeedback and hypnotherapy are also presented. The last section/chapter offers a
comprehensive strategy on how to conduct a structured history taking and physical
exam for orofacial disorders. The guide includes the following sections: Pearls of
Wisdom, Introduction and Diagnostic Subtypes, Clinical Presentation, Etiology,
Epidemiology, Pathophysiology and Mechanisms, Diagnosis and Diagnostic
Criteria, Rationale for Treatment, Treatment Options, Treatment Goals and
Sequencing of Care, and References.
We hope this guide is helpful to your daily care of patients with these disorders.
Sincerely,
João N.A.R. Ferreira Singapore, Singapore
James Fricton Edina, MN, USA
Nelson Rhodus Minneapolis, MN, USA
vii
In Memoriam
To Dr. Sol Silverman, Dr. Jonathan Ship, and Dr. Steven Graff-Radford our
compassionate colleagues and enthusiastic educators.
ix
Contents
Part I Oral Cancer and Premalignant Lesions

1 Leukoplakia�� 3
Isaäc van der Waal
2 Oral Cancer�� 15
Douglas E. Peterson and Nelson L. Rhodus
3 Orofacial Pain in Cancer�� 21
Gary D. Klasser and Joel Epstein
Part II Oral Mucosal Diseases

4 Herpes Simplex�� 35
Andres Pinto
5 Oral Vesiculobullous Diseases �� 41
Francina Lozada-Nur and Chelsia Sim
6 Oral Candidiasis�� 53
Scott S. De Rossi and Katharine Ciarrocca
Part III Oral Diseases of the Senses

7 Chemosensory Disorders�� 63
Joseph A. D’Ambrosio
8 Oral Malodor�� 71
Patricia Lenton
Part IV Salivary Gland Dysfunctions

9 Salivary Gland Dysfunction and Xerostomia�� 89
Mahvash Navazesh
10 Gene Therapy for Radiation-Induced Salivary Hypofunction�� 95
Bruce J. Baum
xi
xii Contents
11 Salivary Hypofunction in Aging Adults �� 105

Catherine Hong and João N.A.R. Ferreira
Part V Oral Parafunctions and Sleep Disorders

12 Oral Parafunctional Behaviors �� 115
Alan G. Glaros and James Fricton
13 Obstructive Sleep Apnea and Snoring �� 127
Antonio G. Romero and João N.A.R. Ferreira
Part VI Temporomandibular Disorders and Occlusal Dysfunction

14 Temporomandibular Joint Disorders�� 145
Jeffrey P. Okeson, Cristina Perez, and James R. Fricton
15 Temporomandibular Muscle Disorders �� 159
Edward F. Wright
16 Orofacial Dystonias and Dyskinesias �� 171
Gary M. Heir and José L. de la Hoz
17 Occlusal Dysesthesia and Dysfunction �� 189
Somsak Mitrirattanakul, Tan Hee Hon, and João N.A.R. Ferreira
Part VII Orofacial Pain Disorders

18 Non-odontogenic “Tooth” Pain�� 197
Flavia P. Kapos and Donald R. Nixdorf
19 Trigeminal Neuropathic Pain and Orofacial Neuralgias�� 213
David A. Sirois and Teekayu P. Jorns
20 Burning Mouth Syndrome�� 223
Miriam Grushka and Nan Su
Part VIII Headaches

21 Chronic Daily Headache�� 235
Roger K. Cady and Kathleen Farmer
22 Migraine�� 245
Steven B. Graff-Radford
23 Cluster and Facial Headache�� 257
Robert G. Kaniecki
24 Migraine Variants�� 269
Robert L. Merrill
Contents xiii
Part IX Health Care Approaches in Orofacial and Widespread Pains

25 Interdisciplinary and Multidisciplinary Approaches
to Orofacial Pain Care �� 283
Shawn McMahon
26 Transformative Care for Orofacial Disorders �� 301
James R. Fricton
27 Integrative Approaches to Orofacial Pain: Role of Biofeedback
and Hypnosis�� 317
Gabriel Tan, Alan Glaros, Richard Sherman, and Chin Yi Wong
Part X A Comprehensive Approach to Orofacial Disorders

28 History Taking and Physical Examination for
Orofacial Disorders�� 327
David Ojeda Díaz and Thomas P. Sollecito
Part I
Oral Cancer and Premalignant Lesions
Leukoplakia
1
Isaäc van der Waal
Pearls of Wisdom
• Oral leukoplakia is the most common premalignant lesion or disorder of
the oral mucosa.
• The expert clinician is occasionally surprised by the presence of epithelial
dysplasia or even invasive squamous cell carcinoma in a leukoplakia
lesion, irrespective of its clinical presentation.
• The annual malignant transformation rate amounts approximately 1–2%.
Of the many predictors of future cancer development, including a vast
number of genetic and molecular biomarkers, the presence and degree of
epithelial dysplasia is still the most important one.
• Dysplastic leukoplakias in non-smokers carry a higher risk of cancer
development.
• Malignant transformation may also occur in non-dysplastic leukoplakias.
• Spontaneous regression is rather rare. In small lesions, e.g., less than
2–3 cm, the taking of an excisional biopsy is recommended.
• Leukoplakias persisting for more than 3 months should be biopsied at least
once, and, if left untreated, a biopsy should be performed thereafter if clin-
ical changes occur.
• Symptomatic leukoplakias should always be biopsied as soon as possible.
• In case of larger or multiple lesions, surgical removal may be limited to the
clinically most suspicious area, if any, and may be combined with CO2
laser evaporation.
I. van der Waal, DDS, PhD

VU University Medical Centre/ACTA, Department of Oral and Maxillofacial
Surgery/Pathology, P.O. Box 7057, 1007 MB Amsterdam, The Netherlands
e-mail: i.vanderwaal@hotmail.com
© Springer International Publishing AG 2017 3

J.N.A.R. Ferreira et al. (eds.), Orofacial Disorders,
DOI 10.1007/978-3-319-51508-3_1
4 I. van der Waal
• Because of the lack of prospective randomized trials, it is questionable

whether removal of leukoplakias does truly eliminate or reduce the risk of
future development of oral cancer.
• All patients with leukoplakias, being actively treated or not, should be
followed up with intervals of 3–6 months, depending on the histopatho-
logical findings.
1.1 Introduction
Leukoplakia is primarily a clinical term for a predominantly white lesion that can-
not be wiped off and that cannot be characterized as any other definable white lesion
of the oral mucosa. It is the most common premalignant lesion of the oral mucosa.
A premalignant or potentially malignant lesion is a lesion that carries a signifi-
cantly increased risk of transforming into cancer. Some prefer to refer to leukopla-
kia as a disorder instead of a lesion since cancer development may not only occur in
or adjacent to the leukoplakic area but also elsewhere in the oral cavity or the head-
and-neck region.
1.2 Clinical Presentation
• Oral leukoplakias are clinically classified into homogeneous and nonhomoge-

neous leukoplakias.
• Homogeneous leukoplakias are consistently white and flat and usually do not
cause symptoms (Fig. 1.1).
• Nonhomogeneous leukoplakias comprise lesions with a mixture of white and
red changes (erythroleukoplakias) and nodular or speckled leukoplakias
Fig. 1.1 Homogeneous
(flat and thin) leukoplakia
1 Leukoplakia 5
Fig. 1.2 Nonhomogeneous
(erythematous) leukoplakia
(“erythroleukoplakia”)
(nodular) leukoplakia
(Figs. 1.2 and 1.3); these nonhomogeneous leukoplakias usually cause some
discomfort. Another type of nonhomogeneous leukoplakia is the verrucous
leukoplakia in which there is a somewhat exophytic, verrucous texture
(Fig. 1.4). Verrucous leukoplakias are usually asymptomatic. A rare subtype of
verrucous leukoplakia is proliferative verrucous leukoplakia (PVL), character-
ized by widespread occurrence and resistance to treatment. Recurrences of
PVL are, indeed, common and malignant transformation may be inevitable in
many if not all patients [1].
• When redness is the predominant color of a lesion that cannot be recognized as
any other definable red lesion or disorder of the oral mucosa, the term erythro-
plakia is applied (Fig. 1.5). Erythroplakias are usually symptomatic with a local-
ized burning pain. Erythroplakias are less common than leukoplakias, but the
risk of malignant transformation is much higher than in leukoplakias.
6 I. van der Waal
(verrucous) leukoplakia
Fig. 1.5 Erythroplakia of

the palate
1.3 Etiology and Epidemiology
• Oral leukoplakias occur much more often in smokers than in non-smokers.

• Other possible etiologies for oral leukoplakia include Candida albicans and cer-
tain human papillomaviruses.
• Limited information is available on the epidemiology of oral leukoplakia. The
reported prevalence rates vary between 1.0% and 2.7% [2].
• Most affected patients are in the fourth decade of life or above.
• The male-female ratio varies in different parts of the world. In the Western world,
there is no distinct gender predilection.
1 Leukoplakia 7
1.4 Pathophysiology and Mechanisms
• In patients who smoke, the epithelial changes that result in the development of
leukoplakia are thought to be brought about by the carcinogens of tobacco
products.
• In non-smokers with oral leukoplakia, the pathophysiology is currently unknown.
• The possible role of Candida albicans in the development or the malignant trans-
formation of leukoplakia is poorly understood.
• Suggested determinants contributing to malignant potential include advanced
age, female gender, size exceeding 200 mm2, nonhomogeneous clinical type, and
higher grades of epithelial dysplasia [3]. In many of the reported studies, location
on the tongue is another risk factor.
• Apparently, dysplastic leukoplakias in non-smokers carry a higher risk of cancer
development than in smokers [4].
• Of the numerous suggested genetic and molecular biomarkers that may be predic-
tive of future malignant transformation, loss of heterozygosity at 9p and mutated
p53 in biopsies of oral leukoplakias are at present the most promising ones [5, 6].
1.5 Diagnosis and Diagnostic Criteria
• The diagnosis of oral leukoplakia is in most cases primarily based on clinical

aspects.
• White lesions that may be caused by friction, such as vigorously toothbrushing, may
be diagnosed as frictional lesions but only so if the lesions have disappeared after
changing the brushing habits. Otherwise, the term leukoplakia should be applied.
• Occasionally, it may be difficult to distinguish leukoplakia from other white
lesions and disorders (Table 1.1); this particularly applies to the plaque type or
erosive, erythematous type of lichen planus.
• Whitish or reddish changes of the oral mucosa may also be the result of direct
contact with large dental restorations, particularly amalgam, being referred to as
“contact lesions.”
• For diagnostic purposes there is hardly a role for exfoliative cytology, brush
cytology, or vital staining, such as by toluidine blue, except in case of erythroleu-
koplakia or erythroplakia. Nevertheless, the use of toluidine blue staining may
aid in determining the site of the biopsy [7]. Preference is given to one or more
incisional biopsies or, in case of a lesion less than a few centimeters in diameter,
by an excisional biopsy.
• The biopsy should be taken at the site of induration, redness, or symptoms, if
present. In multiple or large leukoplakias, the taking of multiple biopsies should
be considered. The pathologist should be provided with proper clinical informa-
tion, among others with regard to the site where the biopsy has been taken.
8 I. van der Waal
Table 1.1 Definable white lesions and disorders that may have a leukoplakic appearance
Lesion Main diagnostic criteria
Alveolar ridge “keratosis” Primarily a clinical diagnosis of a flat, white change of the
mucosa of an edentulous part of the alveolar ridge; may
overlap frictional lesion (“keratosis”)
Aspirin burn History of prolonged local application of aspirin tablets
(paracetamol may cause similar changes)
Candidiasis, pseudomembranous, Clinical aspect (pseudomembranous, often symmetrical pattern)
hyperplastic Somewhat questionable entity; some refer to this lesion as
candida-associated leukoplakia
Darier-White diseases Associated with lesions of the skin and the nails; rather typical
histopathology
Frictional “keratosis” Disappearance of the lesion within an arbitrarily chosen period
of 6–12 weeks after elimination of the suspected mechanical
irritation (e.g., habit of vigorous toothbrushing); therefore, it is
a retrospective diagnosis only
Geographic tongue Primarily a clinical diagnosis; characterized by a wandering
pattern in time
Glassblower lesion Occurs only in glassblowers; disappears within a few weeks
after cessation of glassblowing
Hairy leukoplakia Clinical aspect (bilateral localization on the borders of the
tongue); histopathology (including EBV immunohistochemical
stain)
Lesion caused by a dental Disappearance of the anatomically closely related (amalgam)
restoration (often amalgam) restoration within an arbitrarily chosen period of 6–12 weeks
after its replacement; therefore, it is a retrospective diagnosis
only
Leukoedema Clinical diagnosis (including symmetrical pattern) of a
veil-like aspect of the buccal mucosa
Lichen planus, reticular type and Primarily a clinical diagnosis (including symmetrical pattern);
erythematous type histopathology is not diagnostic by its own
Linea alba Clinical aspect (located on the line of occlusion in the cheek
mucosa; almost always bilateral)
Lupus erythematosus Primarily a clinical diagnosis (including symmetrical pattern);
almost always cutaneous involvement as well. Histopathology
is not diagnostic by its own
Morsicatio (habitual chewing or History of habitual chewing or biting; clinical aspects
biting of the cheek, tongue, lips)
Papilloma and allied lesions, e.g., Clinical aspect; medical history; HPV typing of a biopsy may
condyloma acuminatum, multifocal be helpful
epithelial hyperplasia, squamous
papilloma, verruca vulgaris
Skin graft, e.g., after a History of a previous skin graft
vestibuloplasty
Smokers’ lesion Disappearance of the lesion within an arbitrarily chosen period
of 6–12 weeks after cessation of the tobacco habits; therefore,
it is a retrospective diagnosis only
Smokers’ palate (“stomatitis Clinical aspect; history of smoking
nicotinica”)
Syphilis, secondary (“mucous Clinical aspect; demonstration of T. pallidum; serology
patches”)
Verrucous hyperplasia and Clinicopathological entities
verrucous carcinoma
White sponge nevus Family history; clinical aspect (often symmetrical pattern)
1 Leukoplakia 9
Fig. 1.6 Mild
a
hyperkeratosis; no
epithelial dysplasia (a);
moderate epithelial
dysplasia (b)
• The pathologist report should include a statement on the absence or presence of

epithelial dysplasia and, if present, its degree. Usually three such grades are rec-
ognized, being mild, moderate, and severe (Fig. 1.6a, b). The difficulties encoun-
tered in establishing a reproducible way of dysplasia grading are well discussed
in a study by Speight et al. [8].
• In rare cases, particularly in erythroplakias, carcinoma in situ or invasive squa-
mous cell carcinoma is seen in a biopsy of a leukoplakic lesion. In such instances
the diagnosis of leukoplakia is replaced by the histopathological diagnosis. In all
other cases a final diagnosis of dysplastic or non-dysplastic leukoplakia remains.
10 I. van der Waal
Fig. 1.7 Leukoplakia of

a
the floor of the mouth; no
treatment instituted (a);
squamous cell carcinoma
developing 4 years later (b)
1.6 Rationale for Treatment
Treatment is directed at removal of symptoms, if any, but above all at prevention of

malignant transformation. Unfortunately, such removal may actually not entirely
eliminate or reduce the risk of future development of oral cancer [9–11]. This also
applies to all other surgical and nonsurgical treatment modalities.
If untreated, transformation into a squamous cell carcinoma occurs at an annual
rate of approximately 1–2%. The absence or presence of epithelial dysplasia, and, if
present, the degree of dysplasia as assessed by histopathological examination of a
biopsy, is at present still the most reliable predictive factor of malignant transforma-
tion. Nevertheless, malignant transformation may occasionally occur in non-
dysplastic leukoplakias, while some dysplastic leukoplakias may remain unchanged
or regress (Fig. 1.7a, b) [12].
1.7 Treatment Options
• Spontaneous regression of oral leukoplakia is rare.

• Possible mechanical and chemical etiologic factors should be eliminated, par-
ticularly any tobacco habits, cheek and mucosal biting, sharp and irritating teeth,
alcohol, and others.
1 Leukoplakia 11
• In lesions that are in close contact with large amalgam restorations, replace-
ment of such restorations, e.g., by composite type of material or porcelain,
should be considered; no reliable tests are available to predict the result of such
replacement.
• Lesions smaller than a few centimeters may be excised or vaporized by CO2 laser
(but only after the taking of a biopsy), although recurrence rates may vary from
10% to 30%; in larger lesions or in case of multiple occurrences, the morbidity
of treatment should be weighted against the relative low risk of malignant
transformation.
• In widespread lesions, surgical intervention (including laser-based) may have to
be limited to the clinically most suspicious part of the leukoplakia.
1.8 Treatment Goals and Sequencing of Care
A flowchart for the sequence of care of oral leukoplakia is showed in Table 1.2.
Nevertheless, the following goals and recommendations should be taken into con-
sideration while managing these lesions:
• Goals of treatment include a healthy mouth and a minimal risk of developing oral
cancer.
• Initial treatment is aimed at cessation of tobacco habits, if any, excessive
intake of alcohol, and reduction of oral habits such as cheek or mucosal
biting.
Table 1.2 Flowchart with the sequence of care for the management of oral leukoplakia
Management of oral leukoplakia
(Provisional clinical diagnosis)
In case of symptoms consider the taking of a biopsy

Elimination of possible cause(s), incl. tobacco habits No possible cause(s)
(No more than 6-12 weeks observation) (Definitive clinical diagnosis)
Good response No response Biopsy

(Definable lesion; (Definitive clinical diagnosis)
e.q. frictional lesion)
· Management accordingly
No epithelial dysplasia Epithelial dysplasia Definable lesion;

(Nondysplastic leukoplakia) (Dysplastic leukoplakia) e.g. lichen planus
· Management accordingly
Treatment, if feasible Treatment indicated

Follow-up at intervals Follow-up at intervals
of six months; lifelong (?) of three months; lifelong (?)
12 I. van der Waal
• Possible other etiologic factors should be eliminated, such as sharp edges of

teeth or large amalgam restorations that are in close contact with the lesion. In
symptomatic cases, it is a safe practice to first perform a biopsy.
• In the absence of etiologic factors or in persisting lesions of more than 3-month dura-
tion, performing one or more biopsies should be considered in an early stage in order
to be informed about the presence and, if so, of the degree of epithelial dysplasia.
• Although removal of leukoplakia may actually not eliminate or reduce the risk of
future development of oral cancer, a wait-and-see policy is for most patients,
particularly in case of a small lesion, not an acceptable strategy. Such strategy
may be more acceptable in non-dysplastic lesions that are too large for simple
excision or (CO2) laser treatment.
• In a few studies, wide surgical excision has resulted in a lower rate of recurrence
and progression to malignancy in comparison to lesions that have been excised
in a more conservative way [13, 14].
• Surgical removal is preferable above laser evaporation because of the availability
of a surgical specimen that allows additional histopathological examination of
the entire leukoplakic lesion.
• Cessation of smoking habits may reduce the risk of unfavorable events after sur-
gical removal of leukoplakias in smokers [15].
• Intervals of follow-up in treated and untreated patients are largely dependent on
the degree of epithelial dysplasia; in the absence of dysplasia, intervals of
6 months seem to be justified, while in case of untreated dysplastic lesions, inter-
vals of 3 months are recommended.
• Follow-up visits are aimed at early detection of recurrences or, in untreated leu-
koplakias, at changes in size, color, or texture of the leukoplakia or the presence
of symptoms.
• No strict rules can be provided for the length of follow-up; in patients in whom
complete removal has been obtained of a non-dysplastic leukoplakia, follow-up
may be completed after 3 years.
References
1. Parashar P. Proliferative verrucous leukoplakia: an elusive disorder. J Evid Based Dent Pract.
2014;(Suppl):147–53.
2. Petti S. Pooled estimate of world leukoplakia prevalence: a systematic review. Oral Oncol.
2003;39(8):770–80.
3. Warnakulasuriya S, Ariyawardana A. Malignant transformation of oral leukoplakia: a sys-
temic review of observational studies. J Oral Pathol Med. 2015; doi: 10.1111/jop.12339. Epub
ahead of print.
4. Ho MW, Risk JM, Woolgar JA, Field EA, Field JK, Steele JC, et al. The clinical determinants
of malignant transformation in oral dysplasia. Oral Oncol. 2012;48(10):969–76.
5. William Jr WN. Oral premalignant lesions: any progress with systemic therapies? Curr Opin
Oncol. 2012;24(3):205–2010.
6. Graveland AP, Bremmer JF, de Maaker M, Brink A, Cobussen P, Zwart M, et al. Molecular
screening of oral precancer. Oral Oncol. 2013;49(12):1129–35.
1 Leukoplakia 13
7. Chainani-Wu N, Madden E, Cox D, Sroussi H, Epstein J, Silverman Jr S. Toluidine blue aids in

detection of dysplasia and carcinoma in suspicious oral lesions. Oral Dis. 2015;21(7):879–85.
8. Speight PM, Abram TJ, Floriano PN, James BS, Vick J, Thornhill MH, et al. Interobserver
agreement in dysplasia grading: toward an enhanced gold standard for clinical pathology trials.
Oral Surg Oral Med Oral Pathol Oral Radiol. 2015;120(4):474–82.
9. Holmstrup P. Can we prevent malignancy by treating premalignant lesions? Editorial Oral
Oncol. 2009;45(7):549–50.
10. Anderson A, Ishak N. Marked variation in malignant transformation rates of oral leukoplakia.
Evid Based Dent. 2015;16(4):102–3.
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in surgery for potentially malignant disorders of the oral cavity? J Oral Pathol Med.
2014;43(4):239–44.
12. Kuribayashi Y, Tsushima F, Morita K, Matsumoto K, Sakurai J, Uesugi A, et al. Long-term
outcome of non-surgical treatment in patients with oral leukoplakia. Oral Oncol.
2015;51(11):1020–5.
13. Kuribayashi Y, Tsushima F, Sato M, Morita K, Omura K. Recurrence patterns of oral leuko-
plakia after curative surgical resection: important factors that predict the risk of recurrence and
malignancy. J Oral Pathol Med. 2012;41(9):682–8.
14. Arnaoutakis D, Bishop J, Westra W, Califano JA. Recurrence patterns and management of oral
cavity premalignant lesions. Oral Oncol. 2013;49(8):814–7.
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Oral Cancer
2
Douglas E. Peterson and Nelson L. Rhodus
Pearls of Wisdom
• Oral squamous cell carcinoma (SCC) is largely a preventable malignancy,
if patients either never use tobacco or permanently discontinue its use.
• Systematic oral examinations by an experienced clinician are important for
early detection and management.
• High durable cure rates (e.g., >90%) occur if the oral SCC is detected in
Stage I.
2.1 Introduction
Oral and pharyngeal squamous cell carcinoma (SCC) is projected to the sixth most
common malignancy [1]. Primary cause continues to be associated with tobacco use
in most but not all cases. Currently, the most rapidly developed oropharyngeal can-
cer is caused by HPV [2, 3]. Thus, it is one of only a few human cancers that are
largely preventable based on current understanding of carcinogenesis.
D.E. Peterson, DMD, PhD

Department of Oral Diagnosis, School of Dental Medicine, Pittsburgh, PA, USA
Oral Oncology Program, Neag Comprehensive Cancer Center, University of Connecticut
Health Center, Farmington, CT, USA
N.L. Rhodus, DMD, MPH, FICD (*)
Division of Oral Medicine, School of Dentistry, University of Minnesota,
Minneapolis, MN, USA
Department of Otolaryngology, School of Medicine, University of Minnesota,
e-mail: rhodu001@umn.edu

DOI 10.1007/978-3-319-51508-3_2
16 D.E. Peterson and N.L. Rhodus
Oral SCC typically both grows relatively slowly and doesn’t metastasize in the
early months of clinical presentation. Over time, untreated oral SCC can gradually
lead to compromised oral function including speech, mastication, and/or use of den-
tal prostheses. Early detection and treatment offers the highest incidence of long-
term survival and minimizes the deleterious impact of the progressing tumor on oral
symptoms and signs including pain.
The most common sites for oral SCC include the posterior lateral tongue and floor
of the mouth, lip, and oropharynx. Pain as a first complaint occurs in up to 66% of
these patients, although lip pain is least frequent (27%) as an initial reason for seek-
ing dental medical evaluation [3]. Importantly, patients are often unaware of the
presence of oral SCC in its early clinical stages (Fig. 2.1). Thus, although pain is
often an initial reason that causes patients to have evaluation, the pain itself may not
occur until several months after clinical appearance of the lesion.
As oral SCC expands in size (Fig. 2.2), pain may develop secondary to trauma
associated with the elevated mucosal surface. This is particularly common when the
lesion involves the posterior lateral tongue (Fig. 2.3), a site easily traumatized dur-
ing normal oral functions.
Fig. 2.1 Early squamous

cell carcinoma of the left
floor of mouth
2 Oral Cancer 17
Fig. 2.2 Advanced
squamous cell carcinoma
of the posterior soft palate
complex
Fig. 2.3 Squamous cell

carcinoma of the posterior
lateral tongue (the most
common location)
Etiology of oral SCC can best be viewed as a multifactorial process [2, 3]. Tobacco
use, with or without alcohol abuse, has classically been identified linked with causa-
tion in >90% of these cancers. However, over the past two decades, there has been
an emerging subset of patients who develop oral SCC without these obvious risk
behaviors. Thus, other mechanisms including genetic alterations, mucosal immune
surveillance, as well as other cofactors have been implicated as well.
Oral and pharyngeal cancers accounted for over 45,000 cases and more than
9,000 deaths in 2015 [1].
The carcinogenesis model for oral SCC includes several components which can be
viewed as strongly, possibly, or weakly associated with actual cancer risk [3].
Strongly associated components include:
• Tobacco use, with or without alcohol abuse

• Loss of p53 suppressor genes
• Activation of proto-oncogenes
• Diminished mucosal immune surveillance
Factors possibly linked to oral SCC carcinogenesis include [3]:
• Deficiencies in antioxidant vitamins and nutrients

• Viruses (herpesviruses, papilloma virus)
Other factors have been investigated relative to their role in carcinogenesis and
have to date not been demonstrated to be important cofactors. These cofactors include:
• Deficiency or excess of dietary proteins, fats, or carbohydrates

• Denture trauma
• Dental radiographs
• Fluoridated water
The gold standard for diagnosis remains incisional or excisional biopsy followed by
histopathologic confirmation [3]. Selection of the biopsy site as well as of the histo-
pathology sections to be interpreted is critically important to maximizing detection
of malignancy. This diagnostic strategy, coupled with additional clinical and radio-
graphic assessment, is typically sufficient to both confirm the final diagnosis and to
define the staging of the patient.
This approach needs to be considered in the context of screening and preven-
tion, as well as the essential need for detailed inspection of the oral mucosa by
a health professional well experienced in detecting subtle physical changes in
the tissue. The requirement for experienced examiners is heightened by the fact
that the oral cancer may be located on oral mucosal tissue that cannot be easily
inspected without careful manipulation of the oral soft tissue. Since many oral
SCCs are located on posterior lateral tongue, floor of mouth, and retromolar
pad, detailed and systematic inspection of all oral mucosal tissues at risk is
required.
2 Oral Cancer 19
Adjunctive diagnostic aids [3] include:
• Toluidine blue oral rinse: metachromatic dye that may enhance selection of
biopsy site when broad field of suspicious tissue is present
• Oral cytology and brush biopsy: minimally invasive technique that can be useful
in determining whether incisional or excisional biopsy may be required
Additional diagnostic strategies including imaging (computed tomography, mag-

netic resonance imaging) are also important regarding staging, once the diagnosis of
oral cancer has been confirmed histopathologically.
Treatment rationale is directed to surgical removal, combined with cytotoxic ther-

apy (radiation with or without chemotherapy) in more advanced cases [3]. Decisions
as to which treatment strategy will be used are principally governed by the follow-
ing considerations:
• Tumor histopathologic diagnosis

• Location of tumor in relation to normal oral hard and soft tissue
• Tumor stage of patient
Stage I tumors are typically removed surgically, with >90% cure rates resulting. No
additional therapy, including radiation therapy or chemotherapy, is generally indi-
cated. Chronic morbidity resulting from the surgery is rare, given the relatively
conservative surgical approach and the location of most tumors [3].
Surgical treatment of more advanced tumors is typically the primary therapeutic
choice as well. If there is evidence of metastasis, radiation therapy with or without
concomitant chemotherapy is indicated.
Treatment may thus be single modality or multimodality, depending on stage:
• Surgical removal is the primary therapy for Stage I and early Stage II (confirm II).
• Surgery followed by radiation is the primary therapy for advanced Stage II and
Stage III.
• Surgical debulking, followed by radiation and concomitant high-dose chemo-
therapy, is frequently utilized for the most advanced stages.
Durable cure is the ideal treatment goal. However, diagnosis of advanced tumors
(e.g., Stage III or IV) results in higher mortality rates sooner, versus cancers that are
diagnosed at an early clinical stage.
For all stages of oral cavity and pharyngeal cancers, approximately 85% of
patients are alive 1 year following diagnosis [1]. Overall, the 5- and 10-year survival
rates are 59% and 44%, respectively [1]. Furthermore, there is a population bias such
that American black men have a disproportionately high 5-year mortality rate [1].
References
1. Siegel RL, Miller KD, Jemal A. Cancer statistics, 2016. CA Cancer J Clin. 2016;65:5–29.
2. Silverman Jr S. Epidemiology. In: Silverman Jr S, editor. Oral cancer. 5th ed. Hamilton: BC
Decker; 2003. p. 1–6.
3. Rhodus NL, Kerr AR, Patel K. Oral cancer: leukoplakia and squamous cell carcinoma (Chapter
6). In: Sollectio TS, editor. Dental clinics of North America. Oral lesions. Saunders:
Philadelphia; vol. 57, issue 3; 2014. p. 143–56. ISBN-978-0-323-28995-5.
Orofacial Pain in Cancer
3
Gary D. Klasser and Joel Epstein
Pearls of Wisdom
• Mild-to-moderate pain is present in the majority of HNC patients at the
time of diagnosis.
• Orofacial pain due to HNC is the most common reason patients seek
diagnosis.
• Pain arising in cancer patients usually have a multifactorial etiology and
require a multidisciplinary management approach.
• The approach to treatment of pain from malignant origin and all cancer
therapies that are pain focused must follow guidelines of WHO analgesic
ladder, including topical therapy for oropharyngeal pain, and use of adjunc-
tive medications and pain management strategies.
3.1 Introduction
Pain in cancer patients may develop due to the primary disease and/or be due to
single or multimodal cancer therapy, all of which can damage epithelial and con-
nective tissues (Table 3.1). Head and neck cancer (HNC) patients report pain
G.D. Klasser, DMD (*)

Louisiana State University Health Sciences Center, School of Dentistry, Department of
Diagnostic Sciences, 1100 Florida Avenue, Box 140, New Orleans, LA 70119, USA
e-mail: gklass@lsuhsc.edu
J. Epstein, DMD, MSD, FRCD(C), FDS RCS (Edin)
Samuel Oschin Comprehensive Cancer Institute, Cedars Sinai Health System,
8700 Beverly Drive, Los Angeles, CA 90048, USA
Division of Otolaryngology and Head and Neck Surgery, City of Hope,
1500 East Duarte Road, Duarte, CA 91010, USA

DOI 10.1007/978-3-319-51508-3_3
22 G.D. Klasser and J. Epstein
Table 3.1 Classification of Orofacial pain due to cancer

orofacial pain in cancer Pain due to direct effects of tumor
patients Orofacial pain due to cancer management
Pain due to chemotherapy, targeted therapy, immunotherapy
Pain due radiotherapy
Pain due to surgery
Orofacial pain due to other etiology
symptoms that often include both nociceptive and neuropathic components.

Noteworthy, is that orofacial pain due to HNC is the most common reason patients
seek diagnosis.
3.2 Clinical Presentation and Diagnostic Subtypes
Mild-to-moderate pain is present in up to 85% of HNC patients at the time of diag-

nosis. In a study by Potter et al. [1], it was reported that pain was identified in 56%
of patients with HNC at diagnosis, and they found mixed nociceptive and neuro-
pathic pain in 93% of those with pain. Pain due to HNC therapy is a well-recognized
adverse effect of treatment. It presents unique challenges due to the extensive inner-
vation of the orofacial region. Additionally, oral intake, swallowing, speech, and
other motor functions of the head, neck, and oropharynx are constant orofacial pain
triggers.
Furthermore, the oral mucosa is susceptible to the effects of systemic chemo-
therapy and regional radiotherapy, often resulting in painful mucositis and neuropa-
thy. Pain due to oropharyngeal mucositis is the most debilitating complaint
impacting quality of life during cancer therapy in HNC patients and in those receiv-
ing hematopoietic cell transplant (HCT). Pain due to oropharyngeal mucositis
impacts all aspects of oral function, including intake of food and medications, and
frequently requires opioid analgesics for pain management. Mucositis may lead to
admission to hospital, prolong hospital admissions, and admission to intensive care.
This may negatively affect cancer treatment as it will delay, interrupt, or discontinue
previously planned cancer therapies.
In a retrospective study of 1,412 patients with oral cancer, pain was identified as the
first sign of cancer in 19%, and pain was commonly reported with tumor recurrence
[2]. Others reported cancer-related pain in 52% of hospitalized patients, with pain
directly related to tumor in 29% and to surgery in 50% [3, 4]. In large surveys of
pain characteristics in cancer including HNC [5, 6], patients experienced pain asso-
ciated with the tumor (87–92.5%) or cancer therapy (17–20.8%) or both.
Mechanistically, as the tumor progresses, pain may progress; unfortunately, diagno-
sis remains common at advanced stage disease rather than at initial presentation,
3 Orofacial Pain in Cancer 23
thereby reducing performance status, increasing anxiety and depressive symptoms,

weakening quality of life, and rising morbidity and mortality.
Optimal pain management requires recognition of etiological/contributing fac-
tors (which may be multiple), an understanding of the neurobiology of pain, and
addressing the components of the patient’s pain. Successful management may
require multidisciplinary approaches to care and must address the complex sensory
and physiologic components, affective and cognitive dimensions, as well as behav-
ioral and sociocultural issues.
Orofacial pain may be due to the following sources:
• Regional disease
• Metastatic cancer with the most common metastases to the head, neck, and oral
cavity from breast, lung, gastrointestinal tract, and prostate cancers
• Oral involvement by systemic cancers (e.g., hematologic malignancies)
• Referral of pain from remote cancer most commonly from the lungs
Pain due to cancer may have multiple causes: may be due to mechanical factors
and biochemical factors (Table 3.2). Leukemia, lymphoma, and multiple myeloma
may cause head and neck manifestations with direct involvement of oral tissues or
secondary infection due to immunosuppression and myelosuppression. Pain may
present as temporomandibular disorders (TMD) as reported in a study of patients
with nasopharyngeal cancer [7]. Orofacial neuropathic pain may occur with tumor
involvement of cranial nerves, with intracranial tumors or as result of cancer
therapy.
Table 3.2 Mechanisms of pain in oncology – mechanical and biochemical processes

Type of pain Processes
Pain due to tumor Mass, ulceration, invasion, pressure,
ischemia, molecular sensitization, and
stimulation
Pain due to Surgery Acute Incision, inflammation, ischemia,
treatment infection, discontinuity, inflammation,
molecular sensitization, and stimulation
Chronic Neuropathy, ischemia, fibrosis,
molecular sensitization, and stimulation
Radiation therapy Acute Mucositis, infection, molecular
sensitization, and stimulation
Chronic Neuropathy, atrophy, hyposalivation,
ischemia, fibrosis, molecular
Chemotherapy/targeted Acute Mucositis, infection, molecular
therapy, immunotherapy sensitization, and stimulation
Chronic Neuropathy, fibrosis, molecular
Pain not related to cancer or cancer therapy
Psychosocial factors
3.4 athophysiology and Diagnosis: Importance

P
on Understanding Mechanisms
3.4.1 Mechanisms of Orofacial Pain from Cancer
Progresses in the study of mechanisms of cancer-related pain are being made [8–18].
The malignant disease may cause pain due to several mechanisms:
• Tissue damage and release of inflammatory and pain mediators (Table 3.3).
• Traction, invasion, or compression of pain-sensitive structures including nerves,
vessels, bone, and skin or mucosal ulceration.
• Malignancy associated with bone pain includes stretching or invasion of perios-
teum, nerve root infiltration, and compression and reactive muscle involvement.
• Ischemia due to obstruction of blood vessels may lead to necrosis and release of
cellular products and cytokines.
• Malignant cells may lead to local release of numerous proteolytic enzymes, sen-
sitizers, and mediators including prostaglandins [19, 20], growth factors, neu-
rotransmitters, interleukins, endothelins, glutamate, calcitonin gene-related
peptide, serotonin, norepinephrine, and prodynorphin. Additionally, there is an
upregulation of expression of COX-2 [21].
• Some cancers including those of the oropharynx may elaborate circulating
humoral factors, including cytokines, that cause central sensitization that may
lead to persisting pain [19–21]. Uric acid production is increased in malignancies
with rapid cell turnover, and with rapid cell kill due to treatment, a decrease in
the threshold for the transient receptor potential vanilloid receptor (TRPV1 – the
capsaicin receptor) and evoke response [22] via the acid-sensing ion channel
(ASIC) receptor family may occur [23, 24].
3.4.2 Mechanisms Due to Nonsurgical Management of Cancer
Chemotherapy may cause neuropathy that may present in the head, neck, and oral
cavity as treatments result in numerous changes to cellular structure and function,
including loss of sensory terminals in the skin, and alterations of membrane
Table 3.3 Mechanisms of pain due to tumor

Tissue damaged Mechanisms
Mucosa Infiltration, ulceration, inflammation, secondary infection
Bone Infiltration, microfractures, inflammation, hypoxia
Muscle Hypoxia, inflammation, spasm, fibrosis
Vessel Traction, compression, obstruction, inflammation
Neural Local sensitization, inflammation, ectopic firing, compression, central
sensitization, reduced descending inhibition
receptors, intracellular signaling, neurotransmission, excitability, and metabolism all

of which can negatively influence neuronal and glial cell phenotypes [25]. Commonly
used neurotoxic agents such as the taxanes (paclitaxel, docetaxel), vinca alkaloids
(vincristine, vinblastine), platinum-based compounds (cisplatin, oxaliplatin), antimi-
totics (methotrexate, cytosine arabinoside, and fluorouracil), thalidomide, and bort-
ezomib and targeted cancer therapies are responsible. Chemotherapeutic drugs
usually affect sensory nerves (positive and negative symptoms), but motor (muscle
weakness and atrophy) and autonomic nerves (hypotension, cardiac conduction
irregularities, impotence, and bowel and bladder involvement) may also be affected
[26]. Interestingly, both small diameter sensory fibers – unmyelinated C fibers and
thinly myelinated A-delta fibers – and large myelinated A-beta fibers are affected by
chemotherapeutic agents with the large fibers being preferentially injured by chemo-
therapeutic agents such as vinca alkaloids, taxanes, and platinum-based compounds.
The timing of presentation of neuropathic symptoms after chemotherapy is quite
variable after cancer therapy. Agents such as cisplatin manifest signs of neuropathy,
which occur about 1 month after the therapy, while oxaliplatin may produce symp-
toms within 30–60 min after the infusion. Neuropathic pain associated with vinca
alkaloids may begin several days after administration and may involve the trigeminal
and glossopharyngeal nerve distributions.
Radiation therapy has also been associated with neuropathic pain. The severity
of the neuropathic pain is related to radiation exposure, the dose of radiation, and
vicinity to major nerves or nerve plexus. The mechanism of radiation-induced neu-
ropathies is not well understood, but possible causes include radiation-induced tis-
sue fibrosis and associated factors such as ischemia, oxidative stress, and
inflammation [27]. Acute symptoms that may present with hypoesthesia and with
triggered neuralgia-like pain occur during therapy but are uncommon. Radiation-
induced neuropathy can present from 6 months to 20 years after receiving treat-
ment. Radiation therapy also results in hypocellular, hypovascular, and hypoxic
tissue leading to reduced capacity of bone to recover from injury leading to risk of
osteonecrosis. The current prevalence rate of osteoradionecrosis is less than 4%.
Pain, bad breath, taste alteration, and trismus are among the major symptoms asso-
ciated with osteonecrosis. The onset varies and may appear decades following
radiotherapy. Recently, reports of necrosis have been seen in patients on antiresorp-
tive therapies (bisphosphonate or monoclonal antibody) and other drugs affecting
vascular function (e.g., bevacizumab, sunitinib). Although no specific studies are
available on the mechanisms of pain in osteonecrosis, it is possible that the isch-
emia, reduced pH, inflammatory mediator release, and secondary infection are asso-
ciated with pain. Secondary bacterial infection and pathologic fracture in
osteonecrosis may occur thereby compounding symptoms. Muscle fibrosis is
another complication associated with radiation therapy (in addition to surgical inter-
vention), and this may lead to change in function of the jaw, which coupled with
stress, and anxiety/depression may result in TMD and pain or complicate pre-
existing TMD. In addition, scar tissue formation may alter local anatomy and func-
tion, leading to pain and dysfunction.
Taste is also altered as an early response to radiation therapy and may present as
a reduction in taste sensitivity (hypogeusia), an absence of taste sensation (ageusia),
or a distortion of normal taste (dysgeusia) [28]. Taste impairment greatly impacts
the quality of life of the patient, and coupled with other radiation therapy-related
comorbidities such as mucositis, hyposalivation, dysphagia, and reduced food
enjoyment, radiation therapy may affect the nutritional status and overall health of
the patient [29, 30]. Ninety percent of all patients experience a loss of taste when the
cumulative dose has reached 60 Gy. Direct radiation damage to the taste buds or
innervating fibers is the proposed caused of taste loss in addition to the reduction in
salivary flow. Histologically, taste buds show signs of degeneration and atrophy at
10 Gy (2 Gy per day), while at therapeutic levels, the architecture of the taste buds
is almost completely destroyed. Taste loss is usually transient, gradually returning
to normal or near normal levels within 1-year postradiation therapy; however, it also
may be prolonged.
Oropharyngeal mucosal pain may be aggravated by hyposalivation and second-
ary mucosal infection (e.g., fungal, bacterial, viral). Pain may also arise in sali-
vary glands due to sialadenitis during early phases of radiation therapy and in
cases of secondary infection of the salivary glands associated with
hyposalivation.
Oral graft versus host disease, a result of donor cells leading to immune-mediated
inflammation and damage of recipient tissues of the host, may involve the mucosa
that is associated with pain and may be associated with hyposalivation that may in
turn lead to mucosal sensitivity, mucosal infection, mucosal ulceration, and risk of
trauma as well as increased risk of salivary gland infection.
3.4.3 Mechanisms Due to Surgical Procedures for Cancer
Acute surgical pain is an easily understood complication of head and neck and
oral pain in cancer patients, and residual neurosensory impairment following
mandibular resection is common, although some recovery may occur over time
(Table 3.3). Postsurgical neuropathy involving anesthesia and dysesthetic, allo-
dynic, and hyperpathic pain which may become chronic occurs following sur-
gery involving cervical procedures which are commonly part of HNC. In addition
to tissue injury from resection of the tumor and radical neck dissection, local
trauma due to endoscopy or intubation may result in oropharyngeal pain. Surveys
of surgically treated cases of oral cancer show chronic pain are common despite
treatment with different classes of analgesics and physical therapy [31, 32].
Shoulder complaints are a common site of pain in HNC patients, followed by the
oral cavity, neck, and temporomandibular joint each accounting for approxi-
mately 5% of postoperative complaints. Orofacial and head and neck complaints
are reported by approximately 50% of treated cancer patients, affecting their
quality of life.
Table 3.4 Cancer therapy and oropharyngeal mucositis

Disease/therapy % of patients
UADTCa RT alone >80% RT
Chemo/RT Up to 100%
Intensive chemotherapy with HCT rescue Up to 75% with HSV prophylaxis
Solid cancers of GI/GU, breast with neutropenia Up to 50% of courses, ulcerative mucositis
inducing chemotherapy in up to 20% of courses
UADTCa upper aerodigestive cancer, RT radiation therapy, Chemo chemotherapy, HCT hemato-
poietic cell transplant, GI/GU gastrointestinal, genitourinary, HSV herpes simplex virus
3.4.4 M
echanisms Due to Secondary Effects from Radiotherapy
and/or Chemotherapy (Mucositis)
Pain may arise as erythema develops during mucositis development and intensifies
with formation of ulceration and/or pseudomembrane presentation (Table 3.4). Oral
pain associated with mucositis in HNC patients and in HCT/leukemia patients com-
monly require opioids for pain management. In HNC patients treated with the com-
bination of radiation and chemotherapy, an increase in pain may be seen at week 3
that may peak at week 5 with persistence due to mucositis with gradual remission
occurring as mucositis resolves [33].
Mucositis and pain due to chemotherapy may arise within 7–10 days of treatment,
with resolution in 1–3 weeks. In addition, mucosal pain may persist long after muco-
sitis resolves and sensitivity persisting at 1-year follow-up is common and may be
related to mucosal atrophy and neuropathy in the treatment volume. Targeted chemo-
therapy may cause neurotoxicity and may also cause mucosal ulceration with aph-
thous-like presentation and result in pain [34, 35]. Further, immunotherapies (immune
check point inhibitors) may stimulate immune/inflammatory reactions leading to pain
presenting in the oral mucosa and oropharynx as part of the gastrointestinal tract [36].
The direct stomatotoxic effect of chemoradiotherapy results in connective tissue
and epithelial changes resulting in generation of free radicals, release of pro-
inflammatory cytokines, and reduced epithelial renewal that may result in mucositis
(Tables 3.3 and 3.5). Studies of potential nociceptive compounds in mucositis have
been considered [37]. Cellular necrosis and apoptosis and secondary inflammation
may enhance pain by nociceptor sensitization and direct stimulation of nociceptors.
Inflammatory substances released from damaged tissue and from inflammatory cells
directly stimulate or increase the excitability of nociceptors. Degranulation of mast
cells and platelets and breakdown of tumor and normal cells may result in release of
cellular contents including histamine and cytokines. Inflammatory mediators directly
activate and sensitize primary afferent nociceptors [37]. Tumor acidity and inflam-
mation also lead to lower pH that may activate proton-induced pain pathways. As
mucositis progresses to ulcerative stages, secondary bacterial colonization may fur-
ther stimulate cytokine release, which may enhance the inflammatory response and
aggravate pain.
Table 3.5 Potential molecular sensitizers and mediators of pain in cancer

Neurotoxicity:
Radiotherapy, chemotherapy, targeted therapies
Cellular necrosis and apoptosis:
Cell contents enhance inflammation and nociception
Tumor acidity and inflammation lower pH, activate proton-induced pain
Inflammatory substances: damaged tissue and inflammatory cells
Cytokines/growth factors:
Tumor necrosis factor (TNF), interleukins (IL-1, IL-6), platelet-derived growth factor
(PDGF), epidermal growth factor (EGF), transforming growth factor (TGF), vasoactive
intestinal peptide (VIP), vascular endothelial growth factor (VEGF), nerve growth factor
(NGF), endothelins
Sensory neurotransmitters:
Serotonin, noradrenaline, bradykinin, substance P, calcitonin gene-related peptide (CGRP),
excitatory amino acids (e.g., glutamate, which activates N-methyl-D-aspartate receptors) and
hydrogen ions (protons), reactive oxygen species
Inflammatory mediators:
Pro-inflammatory cytokines, histamine
Arachidonic acid metabolites: prostaglandins, leukotrienes
Adenosine, adenosine 5′-triphosphate, nitric oxide
Other:
Infection:
Microbial waste products, pH, increase inflammation, pro-inflammatory cytokines,
inflammatory cell activity
COX-2 upregulation
3.4.5 Orofacial Pain Due to Other Etiologies
Pain unrelated to cancer or its therapy includes all types of pain due to pulpal or
periodontal origin and musculoskeletal pain including TMD. Pain occurring in
cancer patients is likely to be associated with heightened anxiety which impacts
pain experience, presentation, and pain behavior. The psychological state influ-
ences all pains, and the longer a patient suffers, the greater the influence of these
factors.
Pain prevention and management will be improved with further understanding of

molecular and neurophysiologic mechanisms underlying the pain complaint [38–
41]. Current management requires assessment of the components of the presenting
pain, treating the primary disease and the components of pain, diagnosis, and treat-
ment of contributing factors of pain.
3.6 Treatment Options, Goals, and Sequence of Care
The approach to treatment of pain from malignant origin and all therapies that are
pain focused should follow guidelines of WHO analgesic ladder, including topical
therapy for oropharyngeal pain (Table 3.6), and the use of adjunctive medications
and pain management strategies (Table 3.7). Several factors may have potential for
a targeted therapy:
• Serotonin
• Norepinephrine
• Substance P
Table 3.6 Current management of orofacial cancer pain

Diagnosis and treatment of primary disease:
Cancer therapy
Diagnosis and treatment of infections:
Herpesviruses, candida, dental and periodontal and salivary gland infection
Symptom management:
Topical agents: anesthetics, analgesics (cytokines, prostaglandins, etc.)
WHO ladder:
Topical anesthetics/analgesics
Analgesics (prostaglandins, COX2)
Nonsteroidal analgesics, acetaminophen
Mild opioid combination agents
Strong opioids and nonsteroidal analgesics, acetaminophen
Adjunctive centrally acting medications:
Anticonvulsants
Antidepressants
Tricyclics, gabapentinoids, serotonin norepinephrine reuptake inhibitors
Anxiolytics, sleep promoters
Muscle relaxants
Adjunctive techniques:
Physical therapy including orofacial appliances, acupuncture, low-level laser therapy
(LLLT), psychological techniques
Assessment and management of hyposalivation
Address dentinal sensitivity
Table 3.7 Additional and complimentary Palliative radiation therapy

pain management techniques in oncology Cold/moist heat applications
Low-level laser therapy
Hypnosis
Acupuncture
Psychological:
Cognitive/behavioral therapy
Distraction techniques
Relaxation/guided imagery techniques
Music therapy; drama therapy
Counseling
• Calcitonin gene-related peptide (CGRP)

• N-methyl-D-aspartate (NMDA)
• Prostaglandins
• COX-2
• Tumor necrosis factor alpha (TNFα)
• Nerve growth factor (NGF)
• Vascular endothelial growth factor (VEGF)
• Nerve growth factor inducible (NGFi)
• Altered tissue pH
• Interleukins
• Nociceptor sensitization and stimulation
These targeted therapies may provide hope for improvement in pain manage-
ment. Multidisciplinary management, rational use of topical and systemic analge-
sics, adjuvant medications, and additional/adjunctive pain management techniques
provide the optimal pain management due to tumor presence and to complications
of cancer therapies.
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2001;2(2):83–91.
Part II
Oral Mucosal Diseases
Herpes Simplex
4
Andres Pinto
Pearls of Wisdom
• A careful history of patients who complain of oral lesions will guide the
astute clinician toward a correct differential diagnosis for herpes simplex.
• Particular attention should be placed to early prodromal symptoms of her-
pes simplex.
• Early treatment (within 24–48 h of the prodromal cycle) of suspicious her-
pes simplex lesions is suggested for the efficacy of systemic treatment.
• Most clinical trial data is derived from studies on HSV-2 or primary infec-
tion cases. Concrete evidence for recurrent herpes labialis or recurrent
intraoral herpes is limited.
4.1 Introduction
The term herpes simplex refers to a subgroup of infectious mucocutaneous diseases

that may affect the craniofacial complex [1]. As occurs with other viral diseases,
herpes simplex infections usually follow up a prodromal stage of malaise, lymph-
adenopathy, itching, burning, or fever [2, 3]. Gastrointestinal symptoms may also be
present. A majority of the population is exposed to this virus in infancy. However,
few individuals manifest clinically oral or dermatologic lesions of primary infection
[1, 4]. Herpes simplex viridae are divided into HSV-1 and HSV-2. Herpes simplex
virus type 1 usually affects the skin or the mucosa above the waistline. This virus is
also associated with meningeal inflammation. Herpes simplex virus type 2 is linked
to anogenital lesions [5, 6].
A. Pinto, DMD, MPH, MSCE, FDS RCS (Edin)

Oral and Maxillofacial Medicine and Diagnostic Sciences, University Hospitals Case Medical
Center and Case Western Reserve School of Dental Medicine, Cleveland, OH, USA
e-mail: andres.pinto@case.edu

DOI 10.1007/978-3-319-51508-3_4
36 A. Pinto
The clinical presentation of infection by both types of HSV is similar and character-
ized by vesicular eruptions followed by erosion of the epithelium. The mucosal
lesions are characterized by irregular superficial ulcers with clear erythematous
margins and coalescing distribution (Figs. 4.1 and 4.2). Primary infection with the
virus in immune-competent patients usually occurs within the initial 6 years of life
[2, 6]. It is possible that, depending on lifestyle and location, primary infection
occurs in patients older than 30 years of age. Most primary infections are character-
ized by prodromal symptoms. The appearance of the mucosal lesions in HSV-1
Fig. 4.1 Herpes simplex

lesions in the upper and
lower lips and perioral skin
characterized by irregular
superficial ulcers with clear
erythematous margins and
coalescing distribution
Fig. 4.2 Intraoral herpes

simplex lesions in the oral
mucosa vestibule
4 Herpes Simplex 37
infection is termed primary gingivostomatitis [7]. The clinical appearance of the

stomatitis is of severe generalized erosion that may impair oral intake. HSV is neu-
rotrophic. Therefore, after primary infection, they remain within a latent stage in
ganglionic and peripheral distributions of facial nerves. The recurrent presentation
of disease can either occur on the lips, nasal cavity or skin, inside the mouth, or
other distribution of the trigeminal nerve. Labial lesions are described as recurrent
herpes labialis.
Typical sites of onset follow the dermatomal distribution of the cranial nerves.
Standard intraoral sites are heavily keratinized tissues that include the hard palate
and gingiva. Clinical lesions usually appear within 24–48 h of the occurrence of
prodromal symptoms. The natural history of infections with HSV is usually of
8–10 days in immune-competent patients. The clinical presentation in immune-
compromised individuals has a broad range of appearances. The ulcers may present
in non-keratinized issue, may affect multiple dermatomes the same time, and may
be extensive in size. Viral infections in immune-compromised patients are the sec-
ond most common opportunistic infection. Therefore, HSV-related infections may
prolong for more than 2 weeks in these individuals if untreated.
Exposure to herpes virus is almost universal and is dependent on geographic loca-

tion, population group, and other lifestyle factors. Early onset in life is characteristic
of primary infection, although primary infection after 60 years of age has been
reported. Exposure to the virus does not directly imply the development of primary
or recurrent clinical infection. Factors such as immune status, exposure to ultravio-
let light, stress, and nutrition may impact the degree of expression of the virus in its
mucosal sequelae. The prevalence of HSV infection in the United States has been
tracked in the past decade. The National Health and Nutrition Examination Survey
(NHANES) reported a decrease prevalence of HSV-2 infection in a stable HSV-1
infection rate in the 1999–2004 cohort. Within this time, the prevalence of HSV-2
infection (serologic) was reported to be 17%, with a 95% confidence interval of
15.8–18.3%. The prevalence of HSV-1 infection was reported to be 57%, with a
95% confidence interval of 55.9–59.5% [8].
4.4 Pathophysiology
Herpes simplex viridae are double-stranded DNA viral particles. The characteristic
neurotropism of this group allows HSV to elude normal immune surveillance.
Besides, proteins like ICP 0 increased resistance to inflammatory mediators such
as interferon. The components of the virus are the core, the capsid, the tegument,
and an outer envelope [9]. The DNA part is a 152 kg base string that can assume
38 A. Pinto
several structural appearances. The virus enters into host cells, replicates in epithe-
lial cells, and causes cell lysis. After replication, the virus moves into the nerve
ending and migrates to one of the several ganglia that include trigeminal, spheno-
palatine, and geniculate ganglions and gains latency by entering neuronal cell
nuclei [9].
4.5 Diagnosis
The diagnosis of acute infection is made by a combination of careful history and

either polymerase chain reaction (PCR) testing, direct fluorescent antibody assay
(DFA) testing, Tzanck smear, viral culture, or tissue biopsy [5, 10]. The most com-
mon diagnostic test is PCR given its high positive predictive value. When biopsies
are performed, histologic findings include giant cells and viral inclusions. Serologic
testing that may prove useful to differentiate primary versus recurrent infection are
IgM and IgG antibody levels against the virus.
The rationale for treatment of herpes simplex infection is based on the limitation of
the replication ability of the virus by interacting with its DNA processing [11].
Current treatments also aim to shorten the duration of mucosal/skin erosions and
reduce pain [11].
Therapeutic options include topical and systemic delivery of antiviral medications.

Currently available evidence-based approaches for adults are described in Table 4.1.
Novel approaches using topical medications as alternative therapy have proven effi-
cacy in pilot clinical trials. The only FDA-approved topical formulations in the
United States are 5% acyclovir and 1% penciclovir [3, 7, 11–13].
Table 4.1 Pharmacological options for herpes simplex treatment

Medication Dosea Precautions
Acyclovir 200 mg 5×/day for 10 days Renal or hepatic impairment, dehydration, elderly
patients
Valacyclovir 1000 mg 2×/day for 10 days Advanced immune suppression, renal impairment
Famciclovir 250 mg 3×/day for 10 days Renal impairment
a
Some evidence of efficacy of single dose of 1,500 mg of valacyclovir or 2 gm twice a day of fam-
cyclovir as abortive approach for recurrent herpes labialis
4 Herpes Simplex 39
4.8 Treatment Goals
The primary treatment goals include limitation of acute discomfort and increasing
the healing rate of lesions. Shortening of the natural history of the viral infection
cycle, accompanied by the improvement in the quality of life, is among the impor-
tant outcome measures used in clinical trials. Systemic therapy should be the initial
line of treatment because it shortens the duration of viral infection dramatically and
is complemented by FDA-approved topical formulations.
References
1. Stoopler ET, Alfaris S, Alomar D, Sollecito TP. Recurrent Intraoral Herpes. J Emerg Med.
2016. pii: S0736-4679(16)30128-7. doi: 10.1016/j.jemermed.2016.05.001. [Epub ahead of
print].
2. Stoopler ET, Sollecito TP. Oral mucosal diseases: evaluation and management. Med Clin N
Am. 2014;98(6):1323–52.
3. Radulescu M. The pharmacologic management of common lesions of the oral cavity. Dent
Clin N Am. 2016;60(2):407–20.
4. Corstjens PL, Abrams WR, Malamud D. Saliva and viral infections. Periodontol 2000.
2016;70(1):93–110.
5. Miller RM. Diagnosis of herpes simplex virus in patients with erythema multiforme. JAMA.
2014;312(10):1060–1.
6. Balasubramaniam R, Kuperstein AS, Stoopler ET. Update on oral herpes virus infections. Dent
Clin N Am. 2014;58(2):265–80.
7. Goldman RD. Acyclovir for herpetic gingivostomatitis in children. Can Fam Physician.
2016;62(5):403–4.
8. Xu F, Sternberg MR, Kottiri BJ, et al. Trends in herpes simplex virus type 1 and type 2 serop-
revalence in the United States. JAMA. 2006;296(8):964–73.
9. Kolokotronis A, Doumas S. Herpes simplex virus infection, with particular reference to the
progression and complications of primary herpetic gingivostomatitis. Clin Microbiol Infect.
2006;12(3):202–11.
10. Sarnoff DS. Treatment of recurrent herpes labialis. J Drugs Dermatol. 2014;13(9):1016–8.
11. Al-Ghazawi FM, Ramien ML, Brassard A, Shear NH, Beecker J. Management of pain associ-
ated with selected conditions in dermatology. Am J Clin Dermatol. 2016;17:463–74.
12. Zhao M, Zheng R, Jiang J, et al. Topical lipophilic epigallocatechin-3-gallate on herpes labia-
lis: a phase II clinical trial of AverTeaX formula. Oral Surg Oral Med Oral Pathol Oral Radiol.
2015;120(6):717–24.
13. Chi CC, Wang SH, Delamere FM, et al. Interventions for prevention of herpes simplex labialis
(cold sores on the lips). Cochrane Database Syst Rev. 2015;(8):CD010095.
Oral Vesiculobullous Diseases
5
Francina Lozada-Nur and Chelsia Sim
Pearls of Wisdom
• Match the level of complexity of the management program with the com-
plexity of the patients and use a clinical team approach (dermatologist,
PCP, oral hygienist) to facilitate success in complex patients.
• Ensuring that focus is on paradigms of self-care and education will enhance
long-term outcomes and maintain positive relationships with the
clinician.
5.1 Introduction
The diagnosis and management of oral vesiculo-erosive diseases (OVEDs) are often
quite complex due primarily to the fact that clinically they can mimic one another
(e.g., oral lichen planus and lichenoid lesions or pemphigus vulgaris and oral ery-
thema multiform). This frequently leads to an incorrect diagnosis and as a result
ineffective selection and use of medications.
Improving clinicians’ recognition and management of OVED is the aim of this
chapter. To begin with, it is important to know that therapeutic approaches vary
among patients and diseases. These therapies are not recipes, and they are ruled by
disease severity and pattern and by the underlying medical condition of the patient.
F. Lozada-Nur, DDS, MS, MPH, BCOM

Division of Oral Medicine, Department of Oro-facial Science, University of California, San
Francisco School of Dentistry San Francisco, San Francisco, CA 99143, USA
C. Sim, BDS, MS, BCOM (*)
Department of Oral Maxillofacial Surgery, National Dental Center, Clinical Lecturer, Faculty
of Dentistry, National University of Singapore, Singapore, Singapore
e-mail: sqxchel@gmail.com

DOI 10.1007/978-3-319-51508-3_5
42 F. Lozada-Nur and C. Sim
Therefore, before starting any therapy, a clinician must first have at least a provi-
sional diagnosis and/or a tissue biopsy (definitive diagnosis). This allows the clini-
cian to know what she/he is treating and be able to select the most effective drug(s)
and/or treatment protocol to treat that particular condition. Furthermore, having the
correct diagnosis will add to patient understanding of what to expect and likely
improve the outcome (prognosis).
Starting therapy without this safeguard increases the chance of therapeutic fail-
ure and the risk of drug adverse side effects, due to poor therapy choices, and wors-
ens patient’s frustrations. Thus, instead of helping patients, one may do just the
opposite by disguising the original diagnosis.
Oral vesiculo-erosive diseases form a group of chronic inflammatory and/or
autoimmune conditions which affect the oral mucous membrane, occasionally
involving other mucous membranes (e.g., genital, esophagus, nasal, eye-
conjunctiva), and/or skin. It is important to remember that the oral mucosa can be
the first site of involvement and should alert the clinician to consider referral to the
appropriate specialist to evaluate the involvement of other sites (e.g., dermatologist,
ophthalmologist, ENT, gynecologist).
In this chapter, we will address the most common entities often seen by the oral
medicine specialist: oral lichen planus (OLP), oral erythema multiforme (OEM),
mucous membrane pemphigoid (MMP), and pemphigus vulgaris (PV).
5.2.1 Common Symptomatology
1. Pain can be spontaneous or triggered by trauma while eating or from toothbrush-

ing or tooth cleaning.
2. Discomfort and swelling, which is proportional to amount of inflammation, pri-
marily on the buccal and gingival mucosa. Swelling is commonly reported by
patients with OLP (especially among those with severe reticular and atrophic
components), OEM, and PV.
3. If a patient reports having a burning sensation, a secondary yeast infection and/
or burning mouth syndrome should be ruled out.
4. Spontaneous bleeding often reported in patients with MMP can be triggered by
trauma (eating and tooth brushing) in all of them, when the gingival mucosa is
involved.
5.2.2 Signs
1. Possess consistent clinical patterns of disease distribution according to each

condition:
Oral Lichen Planus: must have a bilateral and/or symmetrical clinical distribu-
tion. Otherwise, consider lichenoid disease either due to an allergic reaction
or an early sign of dysplasia. Most commonly affected oral sites include
5 Oral Vesiculobullous Diseases 43
buccal mucosa, lateral borders of the tongue, lower labial mucosa, and hard
palate. However, any site can be involved except vermillion border of the lip.
Classic clinical presentation includes bilateral or symmetric lacey-like white
striaes with or without ulcers covered by pseudomembranes and erythema-
tous changes. The lacey-like changes must always be present in OLP, given
that it is a hallmark of the disease (Fig. 5.1) [1].
Oral Erythema Multiforme: as its name suggests, OEM is characterized by
nonspecific erythematous changes. As shown by our studies, and to help
clinicians in recognizing this condition, OEM has been divided into three
clinical groups: intraoral alone, intraoral and lip, and intraoral and skin.
Ulcers tend to be shallow and irregular with well-demarcated margins
anywhere in the oral cavity with or without involving the vermilion border
of the lip [2–4]. However, vermilion border of the lips is a hallmark of
OEM (Fig. 5.2).
Mucous Membrane Pemphigoid: clinically characterized by desquamative gingi-
vitis (a hallmark of MMP), shallow ulcers covered by pseudomembrane, and
tense or sluggish looking bullae filled with blood, often on the gingival
mucosa, soft palate, and buccal mucosa (Fig. 5.3). These bullae can be painful
due to pressure caused by blood [5, 6].
Fig. 5.1 Oral lichen planus (OLP) located bilaterally on buccal mucosa with typical diffuse, white
reticular striations
Fig. 5.2 Oral erythema multiforme (OEM) with a characteristic generalized crusting of the lips
with multifocal ulcerations within the oral cavity
Fig. 5.3 Mucous membrane pemphigoid (MMP) showing generalized pseudomembrane-covered

ulcers involving both keratinized and nonkeratinized mucosa. Gingival involvement is common
Fig. 5.4 Pemphigus vulgaris (PV). Generalized epithelial sloughing with extensive erosions on
bilateral mandibular buccal sulcus and buccal mucosa
Pemphigus Vulgaris: clinically characterized by true and deep erosions and

edema affecting the buccal mucosa, often with a bilateral distribution
(Fig. 5.4). PV can affect any site of the oral cavity, and it is very painful when
affecting the lateral tongue, soft palate, and esophageal area. By and large oral
lesions precede skin, on average by 3–6 months. In severe cases, PV may
affect the vermilion surface of the lip, which leads to a misdiagnosis of OEM.
Paraneoplastic pemphigus (PNPV) is a different entity from PV and is indica-
tive of an underlying malignancy, which clinically mimics oral erythema mul-
tiforme. However, it has a more aggressive clinical presentation and fails to
respond to conventional treatment for OEM.
2. Extraoral sites, which shall be evaluated include:

• Ocular and nasal (MMP, PV)
• Genital (OLP, MMP, PV)
• Skin (OLP, OEM, MMP, PV)
• Vermilion border of the lip (OEM, PV, PNPV)
3. Chronic clinical course (OLP, MMP, PV)
4. Chronic clinical course with a cyclic pattern of occurrence (OEM)
The prevalence of OVED is unknown due to its rarity as well as clinical variability.
Lack of population-based epidemiological studies makes it difficult to know the true
incidence and prevalence of OVED. However, based on several observational stud-
ies performed in some tertiary centers, rough estimates are reported, depending on
geographic distribution:
• OLP: Prevalence varies from 0.22% to 5% worldwide; incidence of up to 2.2%.

OLP occurs in those between 30 and 80 years of age, with greater prevalence in
females [1, 7, 8].
• MMP: Incidence varies from 1 in 12,000 to 1 in 20,000 of the adult population.
• PV: Incidence varies from 0.1 to 0.5 in 100,000 of the adult population, influenced
by geographic location and ethnicity, higher rates in India, Southeast Europe, and
the Middle East as well as among Jews especially the Ashkenazi Jews.
• OEM: Incidence and prevalence varies widely, from 1.1% to 3.7%, and tends to
occur in young adults between 20 and 50 years of age, with no sexual predilec-
tion or race [2–4].
5.3.1 Etiological Considerations According to Each Condition
OLP: Etiology unknown.
• Potential triggering factors include local and systemic inducers of cell-mediated

hypersensitivity (e.g., dental materials, flavoring agents), stress, and autoimmune
response to epithelial antigens etc. [9].
MMP: Genetic predisposition and environmental factors [6].
• Virus or drugs with structural similarity to endogenous antigens of the BMZ

• HLA-DQB1**0301 allele
PV: Genetic predisposition with environmental factors.
• Drugs such as penicillamine, antibiotics, ACE inhibitors, and NSAIDs.

• Ultraviolet exposure.
• HLAD-R4 and DR14; HLA-DRB1 0402 is associated in Ashkenazi Jews, and

DRB1 1401/04 and DQB1 0503 are associated in non-Jewish patients of
European or Asian descent.
OEM: Etiology unknown.
• Environmental factors
–– Drugs (e.g., antibiotics, anticonvulsants, antihypertensives, diuretics, sulfa
drugs, nonsteroidal anti-inflammatory drugs, birth control pills)
–– Alcohol
–– Endocrine triggers
–– Local or systemic infections:
• Viral: HSV, EBV, HCV, HIV
• Bacterial: Mycoplasma pneumoniae, Mycobacterium leprae
• Fungal: Candida albicans
• OLP: Studies suggest that OLP is a T-cell-mediated autoimmune disease in

which cytotoxic T cells react against epithelial keratinocytes [1, 10–12].
• MMP: Studies show that MMP is a type II, cytotoxic autoimmune disease with auto-
antibodies targeted at BP180, laminin 5 and 6, VII collagen, and beta 4 integrin.
• PV: Studies show that PV is a type II, cytotoxic autoimmune mucocutaneous
disease with autoantibodies targeting to intercellular adhesion molecules, desmo-
glein 3 (dsg3) and desmoglein 1 (dsg1). PV with only oral involvement involves
dsg3, while in both oral and skin involvement, dsg1 and dsg3 are targeted.
• OEM: Studies suggest that OEM is a result of a type IV, T-cell-mediated hyper-
sensitivity reaction to triggering factors [13].
Some of the comorbid conditions and complicating factors may include:
• Medication from underlying chronic medical conditions, specifically high blood

pressure medication, cholesterol-lowering agents, antihyperglycemic agents, and
antidepressants
• Oral candidiasis
• Psychological factors such as stress, anxiety, and depression
5.5.1 Clinical Diagnostic Criteria for OVED
• The presence of persistent shallow ulcers or erosions covered by yellowish-white

fibrinous exudate with surrounding erythematous mucosa.
• Rarely seen are blood-filled bullae or blisters on attached and free mucous
membrane.
• Desquamative gingivitis may be observed in OLP and MMP; in the former, usu-
ally white striations are present.
• For OLP, post-inflammatory hyperpigmentation of the involved oral mucosa may
be observed especially in dark-skinned patients.
5.5.2 Laboratory Diagnostic Criteria for OVED
Routine histological examinations using hematoxylin and eosin (H&E) stains are
to be performed, and at times, direct immunofluorescence and serologic tests are
carried out to aid in diagnosing OVED. Location of tissue obtained for histopatho-
logical examination is crucial in order for the test to be diagnostic. For MMP and
PV, peri-lesional tissue with intact mucosa should be submitted for H&E and direct
immunofluorescence tests. Specimens for DIF are submitted in Michel’s solution.
Serologic tests such as indirect immunofluorescence or ELISA involve collection
of patients’ blood to detect circulating autoantibodies that bind to epithelial
antigens.
5.6 Treatment
5.6.1 Rational for Treatment
Treatment is aimed at controlling sign and symptoms and to prevent disease

progression.
5.6.2 Treatment Options
• Once diagnosis is established, patients should be referred to an oral hygienist to

have a thorough oral prophylaxis and be instructed on proper oral hygiene/ home
care.
• Treatment approach should be determined by disease severity and patient’s med-
ical history (Table 5.1).
• Disease limited to the mouth should be managed with high-potency topical ste-
roids and/or intralesional injections (OLP, OEM, MMP) and good oral hygiene.
Disease involving other mucous membrane and/or skin (OLP, MMP, and PV)
should be treated with a combination of systemic and topical medication
(Table 5.2) [16, 18].
• The most severely involved site should determine treatment course.
• Regular oral hygiene (3–4 months) is crucial, especially early on in the course of
treatment when symptoms prevent the patient from optimal oral care.
Table 5.1 Biopsy, histological, and immunofluorescence findings according to each OVED
condition
Location of tissue
OVED biopsy Routine H&E DIF IIF
OLP Lesional tissuea for Hyperparakeratosis, Deposition of NA
H&E and DIF acanthosis with sawtooth fibrinogen in a
rete ridges; atrophic shaggy pattern
epithelium or ulceration, along the
depending on clinical basement
features membrane
Cytoid bodies (civatte zone (BMZ) in
bodies) within surface the absence of
epithelium IgG, IgM, IgA,
Band-like chronic and C3
inflammatory infiltrates
subjacent to surface
epithelium, predominantly
lymphocytes
Basal liquefactive
degeneration
MMP Peri-lesional tissue Separation of epithelium Deposition of Circulating IgG
adjacent to from underlying IgG ± C3 in themay be present in
erosions/bullae for connective tissue with basement approximately 20%
H&E and DIF preservation of basal membrane of cases
Blood for IIF keratinocytes zone in a No correlation
Scant chronic smooth, between antibody
inflammatory infiltrate in continuous titers and disease
lamina propria linear pattern activity
At times, IgM, Less likely to
IgA, and detect
fibrinogen can autoantibodies in
be present those with
localized oral
lesions than those
with oral and skin
involvement
PV Peri-lesional tissue Intraepithelial cleavage Deposition of Circulating IgG
adjacent to with acantholysis (Tzanck IgG at the targeted at
erosions/bullae for cells) in the suprabasal epithelial intercellular
H&E and DIF region intercellular molecules in active
Blood for IIF Retention of basal spaces, giving disease
keratinocytes along the a “chicken- Antibody titers
basement membrane zone, wire” pattern. may or may not
giving rise to “row of Staining with correlate with
tombstones” C3 may also be disease activity
Sparse inflammatory present May not be useful
infiltrate in the lamina for monitoring
propria with eosinophils response to therapy
Table 5.1 (continued)
Location of tissue
OVED biopsy Routine H&E DIF IIF
OEM Peri-lesional tissue Intraepithelial and Only if needed NA
adjacent to intracellular edema to rule out
erosions/bullae for Increase vascularity with MMP or PV
H&E and DIF perivascular inflammatory
infiltrates in the lamina
propria
Numerous eosinophils
seen
H&E hematoxylin and eosin, DIF direct immunofluorescence, IIF indirect immunofluorescence,
Ig immunoglobulin, C3 complement 3
a
Lesional tissue: avoid ulcerated areas unless suspicious for malignancy
Table 5.2 Treatment approach based on disease severity

Disease severity Induction therapy (2–4 weeks) Maintenance therapya
Severe OVED Prednisone (60 mg a.m. QD) until Start to phase out prednisone to an
Pain >8 scale of 10 50–75% remission of signs and intermediate dose (45–50 mg a.m.
Signs >80% symptoms occurs (average time – 3 QD or QOD), with azathioprine
Involvement weeks), together with daily 150 mg QD or Cellcept 3 gm QD
azathioprine 150 mg QD or Cellcept 3 HPTS BID QD or QOD
gm QD [14]
Moderate OVED Prednisone (50 mg a.m. QD.) until Prednisone 50 or 40 mg a.m. QD
Pain 5 scale of 10 50–75% reduction of signs and or QOD. If patient has a setback,
Signs >50% symptoms is seen. Consider adjunct increase dose to 60 mg QD for
therapy if patient shows early side 2–4 days, and start azathioprine
effects. Curcuminoids 6000 mg/d in 3 100 mg or Cellcept 2.5 gm
divided doses [15] QD. HPTS three times QD
Mild OVED Fluocinonide oint in Orabase 1:1 HPTS BID or QD or QOD
Pain <5 scale 10 clobetasol prop. oint. in Orabase 1:1 depending on disease control or
Signs <25% (0.025%)TID [16] Curcuminoids 6000 mg/d in 3
Tacrolimus powder Orabase 1% divided doses [15]
Prednisone 50 mg am QD for 10 days
followed by HPTS [17]
Gingival lesions Use trays if disease is confined to the Custom-made soft or hard trays
hard palate and gingival mucosa. for HPTS application, to use one
Custom-made vinyl trays for HPTC or tray at a time QOD and QO week
Tacrolimus powder Orabase 1% to be
worn one tray at a time for up to 5 min
TID until complete healing is achieved
HPTS high-potency topical steroids
Cellcept prescribed to patients unable to tolerate azathioprine
Avoid food known to irritate the mouth
Avoid antimicrobial mouth rinse such as chlorhexidine and Listerine® because of their alcohol
content
Monitored for yeast infection while on HPTS
a
Maintenance therapy should be considered after condition is 80–90% under control
5.6.3 Home Care
• Maintain good oral hygiene.

• Eat a bland-soft diet when mouth flares up, and avoid any food known as irritat-
ing the mucosa (spicy, salty, acidic, rough).
• See your dentist once a year and dental hygienist two to three times a year.
• Eat a balanced diet, especially rich in vitamin C.
5.6.4 Pharmacotherapy
• Steroidal anti-inflammatory drugs:

–– Systemic prednisone
Dose: should be taken as a single dose AM, to minimize side effects. Starts on
alternate-date (QOD) therapy as soon as disease is 50% under control.
Precautions: multiple side effects if taken for prolonged period of time such
as headaches, sleep disturbance, increased appetite and weight-gained,
depression, bone loss (long-term use), etc. [19–22].
–– High-potency topical steroids:
Fluocinonide oint 0.05% in Orabase (0.025%) [18].
Clobetasol oint 0.05% in Orabase (0.025%) [23].
• Azathioprine, a cytotoxic drug:
–– Dose: azathioprine 50 mg tablets QD (up to 150 mg QD).
–– Precautions: several side effects may occur when taken on high doses such as
bone marrow suppression and liver toxicity. Always do a base line CBC and
liver test, and repeat during the course of therapy. First week after initiating
therapy, 2-week later, once a month, every 3 months [14].
• Mycophenolate mofetil is an immunosuppressive drug used for the treatment of
severe PV:
–– Dose: Cellcept up to 3 g per day.
–– Precautions: several side effects have been reported such as bone marrow sup-
pression and immunosuppression. Good replacement for azathioprine in
patients who show increase of liver enzymes.
• Tacrolimus and pimecrolimus are calcineurin inhibitors, which result in down-
regulation of the immune response. Both have been approved by the FDA for use
in atopic dermatitis:
–– Dose:
• Tacrolimus powder in Orabase 0.1% TID [17].
• Pimecrolimus cream 1%, apply BID on ulcer [24].
–– Precautions: there is a risk of systemic absorption, especially when used on
large ulcerated areas. However, it is a relatively safe anti-inflammatory topical
medication. Patients may report headaches and local burning sensation.
5.6.5 Treatment Goals and Sequence of Care
• Goals of treatment include:

1. Reduce or eliminate pain.
2. Promote healing.
3. Increase disease-free period.
4. Restore quality of life.
• Short-term strategy is to restore normal eating habits and quality of life.
• Long-term strategy includes reducing recurrence of signs and symptoms of
disease.
• Acute cases of recent onset should be aggressively treated to minimize the need
for long treatments and adverse effects.
• Educate patient on home-care strategies such as optimal home care, oral hygiene,
healthy eating habits, and bland-soft diet when needed as well as minimize expo-
sure to agents and/or factors that induce flares.
References
1. Chianini Wu N, Silverman S, Lozada-Nur F, Mayer P, Watson J. Oral lichen planus: patient
profile, disease progression and treatment responses. J Am Dent Assoc. 2001;132:901–200.
2. Lozada F, Silverman S Jr. Erythema multiforme: clinical characteristics and natural history in
50 patients. Oral Surg Oral Med Oral Pathol. 1978;46:628–36.
3. Lozada-Nur F, Gorsky M, Silverman S Jr. A follow-up study in 96 patients with oral erythema
multiforme. Oral Surg Oral Med Oral Pathol. 1989;67:36–41.
4. Ayangco L, Rogers RS 3rd. Oral manifestations of erythema multiforme. Dermatol Clin.
2003;21(1):195–205.
5. Silverman S Jr, Gorsky M, Lozada-Nur F, Liu A. A follow-up study in 65 patients with mucous
membrane pemphigoid. Oral Surg Oral Med Oral Pathol. 1986;61:233–7.
6. Chan LS, Ahmed AR, Anhalt GJ, Bernauer W, Cooper KD, Elder MJ, Fine JD, Foster CS,
Ghohestani R, Hashimoto T, Hoang-Xuan T, Kirtschig G, Korman NJ, Lightman S, Lozada-
Nur F, Marinkovich MP, et al. The first international consensus on mucous membrane pem-
phigoid: definition, diagnostic criteria, pathogenic factors, medical treatments, and prognostic
indicators. Arch Dermatol. 2002;138:370–9.
7. Lozada-Nur F, Miranda C. Oral lichen planus: pathogenesis and epidemiology. Semin Cutan
Med Surg. 1997;16:290–5.
8. Chan, L, Olivry, T, Lozada-Nur, F. Oral manifestations of autoimmune blistering diseases from
dermatology/diseases of the oral mucosa. e-medicine.com. 2001.
9. Chanaini-Wu N, Lozada-Nur F, Terrault N. Oral lichen planus and hepatitis C. A review. Med
Oral Pathol Oral Radiol Endod. 2004;98(2):171–83.
10. Bramanti TE, Dekker NP, Lozada-Nur F, Sauk JJ, Regezi JA. Heat shock (stress) proteins and
gdT-lymphocytes in oral lichen planus. Oral Surg Oral Med Oral Path. 1995;80:698–70.
11. Regezi JA, Dekker N, MacPhail L, Lozada-Nur F, et al. Vascular adhesion molecules in oral
lichen planus. Oral Surg Oral Med Oral Path. 1996;81:682–90.
12. Ramirez-Amador V, Dekker NP, Lozada-Nur F, Mirowski GW, MacPhail LA, Regezi

JA. Altered interface adhesion molecules in oral lichen planus. J Oral Dis. 1996;2:188–92.
13. Mirowski GW, Lozada-Nur F, Dekker NP, MacPhail LA, Regezi JA. Altered expression of
epithelial integrins and extracellular matrix receptors in oral erythema multiforme. J Cutan
Pathol. 1996;23:473–8.
14. Lozada F. Prednisone and azathioprine in the treatment of oral inflammatory mucocutaneous
diseases. Oral Surg Oral Med Oral Pathol. 1981;52:257–60.
15. Chainani-Wu N, Madden E, Lozada-Nur F, Silverman S. High-dose curcuminoids are effica-
cious in the reduction in symptoms and signs of oral lichen Planus. J Am Acad Dermatol.
2012;66:752–60.
16. Lozada-Nur F, Miranda C. Topical and systemic therapy for oral lichen planus. Semin Cutan
Med Surg. 1997;16:295–300.
17. Lozada-Nur F, Stroussi H. Tacrolimus-powder in Orabase 0.1% for the treatment of oral lichen
Planus and lichenoid reactions: a open clinical trial. Oral Surg Oral Med Oral Pathol Oral
Radiol Endod. 2006;102:744–9.
18. Lozada F, Silverman S Jr. Topically applied fluocinonide in adhesive base in the treatment of
oral vesiculoerosive diseases. Arch Dermatol. 1980;116:898–901.
19. Frey FJ, Amend WJC Jr, Lozada F, Frey BM, Benet LZ. Endogenous hydrocortisone, a pos-
sible factor contributing to the genesis of Cushingoid habitus in patients on prednisolone.
J Clin Endocrinol Metab. 1981;53:1076–80.
20. Benet LZ, Frey FJ, Amend WJC, Lozada F, Frey BM. Endogenous and exogenous gluco-
corticoids in cushingoid patients. Drug Intell Clin Pharm. 1982;16:863–8.
21. Lozada F, Frey F, Benet L. Prednisone clearance: a possible determinant for gluco-corticoid
efficacy in patients with oral vesiculo-erosive diseases. J Dent Res. 1983;62:575–7.
22. Lozada-Nur F, Silverman S Jr, Migliorati C. Adverse side effects associated with prednisone in
the treatment of oral inflammatory ulcerative diseases. JADA. 1984;109:269–70.
23. Lozada-Nur F, Miranda C, Maleski R. A double blind clinical trial on the efficacy and toxicity
of clobetasol ointment in Orabase and fluocinonide ointment in Orabase for the treatment of
chronic oral inflammatory diseases. Oral Surg Oral Med Oral Pathol. 1994;77:598–604.
24. Mc Caughey C, Machen M, Bennet R, et al. Pimecrolimus 1% cream for erosive oral lichen
planus: a 6-week randomized, double-blind, vehicle controlled study with a 6-week open-label
extension to assess efficacy and safety. J Eur Acad Dermatol. 2011;9:1061–7.
Oral Candidiasis
6
Scott S. De Rossi and Katharine Ciarrocca
Pearls of Wisdom
Important facts about oral candida infections:
• Commonly cause acute or chronic multiple lesions.

• Are caused by an opportunistic unicellular yeastlike fungus, a natural
inhabitant of the oral microbial flora in over 50% of healthy individuals.
• Are related to xerostomia, diabetes, immunosuppression, use of broad
spectrum antibiotics.
• Clinical diagnosis can be confirmed with gram stain and culture.
6.1 Introduction
Candida infections involving oropharynx and oral mucous membranes are fairly
common. The majority of these cases are associated with Candida albicans.
Frequently, oropharyngeal candida can be asymptomatic or associated with oral
soreness, dysgeusia, dysphagia, or odynophagia [1]. Over 50% of individuals carry
Candida albicans as a normal commensal organism. Oral candida is often consid-
ered an opportunistic infection, which grows as either yeasts or hyphae. Candida
typically colonizes the mucocutaneous surfaces, but these can be portals of entry
S.S. De Rossi, DMD (*)

Oral Health and Diagnostic Sciences, UNC School of Dentistry,
Office of the Dean, Koury Health Sciences Building, 385 S. Columbia St, CB 7450,
Chapel Hill, NC 27599, USA
e-mail: scott_derossi@unc.edu
K. Ciarrocca, DMD, MSEd
Oral Health and Diagnostic Sciences, Augusta University Dental College of Georgia,
1120 15th Street GC 2254, Augusta, GA 30912, USA

DOI 10.1007/978-3-319-51508-3_6
54 S.S. De Rossi and K. Ciarrocca
into deeper tissues when host defenses are compromised [2]. Species other than C.
albicans are seen increasingly in immunocompromised patients. Candida though is
more commonly seen in the following groups or associated with:
• Women
• Blood type
• High carbohydrate diets
• Xerostomia
• Broad-spectrum antibiotic use
• Denture wearers
• Smokers
• Immunocompromised patients
• Hospitalized patients [1–3]
There are six clinical oral presentations of candida (Table 6.1) [1, 3]:
Table 6.1 Summary of common clinical manifestations of candida

Pseudomembranous “Thrush”
candidiasis White or yellowish cheese-like plaques, easily removed occasionally
leaving a bleeding mucosal base
Mucobuccal folds most common site
Usually appears in early stages of immune suppression
May be accompanied by burning sensation, pain, and difficulty swallowing
Atrophic Generalized erythematous, atrophic areas on any mucosal surface
candidiasis “Kissing lesions” affecting the palate and tongue
May be present the entire course of HIVD but is usually the first to
appear during mild immunosuppression
Usually asymptomatic but can be painful or ulcerative
Hyperplastic A more chronic form of pseudomembranous candida
candidiasis White, confluent patches not easily removed
Associated with severe immunosuppression and xerostomia
Painful chewing/swallowing and persistent dysgeusia
Angular cheilitis Inflammation at the commissures of the lip
Very common; M=F; usually adults
Predisposing factors: smoking, dry mouth, deficiency states,
malabsorption states, immune deficiency
Candida and staph aureus
Mechanical factors play a role
Median rhomboid Central papillary atrophy at mid-dorsum
glossitis Relatively uncommon
No age, gender, or geographic predilection
Rarely sore – usually incidental finding
Usually incidental finding
Denture-related Mild inflammation of the mucosa beneath a denture
stomatitis Papillary erythema on denture-bearing areas
Usually complete upper denture
Chronic wear of denture and underlying systemic disease
6 Oral Candidiasis 55
1. Pseudomembranous candidiasis commonly referred to as “thrush” manifests as

white cheese-like plaques, easily removed occasionally leaving a bleeding
mucosal base (Fig. 6.1).
2. Atrophic candidiasis manifests as generalized erythematous, atrophic areas com-
monly resulting in “kissing lesions” affecting both the palate and tongue simul-
taneously (Fig. 6.2).
3. Hyperplastic candidiasis, which often presents as white, confluent patches, is not
easily removed (Fig. 6.3).
Fig. 6.1 Thrush/
pseudomembranous
candida
Fig. 6.2 Erythematous
candida of the hard palate
in HIVD
Fig. 6.3 Hyperplastic
candida in HIVD
4. Angular cheilitis manifests as erosive, erythematous, painful areas at the lip

commissures with bacterial superinfection (e.g., staphylococci and streptococci)
(Fig. 6.4).
5. Median rhomboid glossitis presents as a central papillary atrophic area at the
middorsal surface of the tongue (Fig. 6.5).
6. Denture-related stomatitis manifests as inflamed red mucosa under denture-
bearing areas (Fig. 6.6).
Fig. 6.4 Angular cheilitis
Fig. 6.5 Median rhomboid

glossitis
Fig. 6.6 Denture-
associated stomatitis
Table 6.2 Prevalence of common Species Percent of cases (%)

candidal species [3–5]
Candida albicans 50–60
Candida glabrata 15–20
Candida parapsilosis 10–20
Candida tropicalis 6–12
Candida pseudotropicalis <5
Candida guilliermondii <5
Candida krusei <5
Candida lusitaniae <5
Candida dubliniensis <5
Candida stellatoidea <5
Although candidal carriage in the oral cavity may be a normal occurrence in a

majority of individuals, candidiasis infection is a result of candida overgrowth.
The most common pathogenic species of candidiasis is Candida albicans,
occurring in 50–60% of cases. Less commonly identified strains are more fre-
quently found in immunosuppressed populations. Greater than 15% of oral can-
didiasis is caused by non-albicans species in those with HIV [2]. Similarly, 46%
of cases of oral candidiasis in patients with malignancy are caused by non-
albicans species [4, 5].
The prevalence of candidal species is listed in Table 6.2.
Candida albicans can be differentiated serologically into A and B serotypes with

equal distribution in healthy individuals with a significant shift to type B in immu-
nocompromised patients. Multiple host defenses, including the oral epithelium
barrier, microbial interactions and oral flora competition, salivary nonimmune
defenses and salivary components with antimicrobial activity, local and systemic
immune defenses, etc., play a role in the development of or resistance to candida
infections [1, 3].
Risk factors for active infection can be divided into endogenous and exogenous
causes [1–4]:
1. Endogenous causes:
• Infancy
• Aging
• Pregnancy
• Immunocompromised states
• Diabetes mellitus
• Sjögren’s syndrome-induced xerostomia
• Vitamin deficiencies
2. Exogenous causes:
• Poor nutrition
• Cigarette smoking
• Ill-fitting oral prostheses
• Localized radiotherapy
• Malignancy with chemotherapy
Candidiasis of the oral cavity can be broadly categorized as primary or secondary.

Primary candida infections involve the oral or perioral tissues, whereas the second-
ary candida characterizes systemic candidiasis that secondarily involves the oral
cavity. Primary oral candidiasis has been traditionally subdivided into acute pseudo-
membranous candidiasis, acute atrophic candidiasis, chronic hyperplastic candidia-
sis, chronic atrophic candidiasis, median rhomboid glossitis, angular cheilitis, and
linear gingival erythema [2].
Candida infection is usually a clinical diagnosis. However, the diagnosis can be
complicated by number of carriers especially when culture is used instead of cytol-
ogy. Identification of blastospores and pseudo-hyphae in stained smears is effective
for a quick diagnosis. Culture, PCR studies, and histology stained with periodic
acid-Schiff may occasionally be necessary [2].
Oral manifestations of candidiasis vary greatly. The differential diagnosis for
oral candidiasis is broad and includes lichen planus, herpes infection, hairy leuko-
plakia, erythema multiforme, anemia and other vitamin deficiencies, chemotherapy-
related mucositis, and vesiculo-ulcerative diseases [2, 6–7].
• Initial management should begin by eliminating predisposing factors identified

during the interview and examination. Despite adequate antifungal treatment,
recurrences are common in patients in whom the underlying risk factors are not
eliminated.
• In cases in which the diagnosis of candidiasis is apparent, empiric treatment can
be undertaken.
• In cases resistant to initial therapy, one should consider culture and sensitivity
testing.
• If the diagnosis is uncertain, a biopsy for evaluation of the fixed tissue should be
obtained.
• Parenteral antifungal agents are generally not used to treat isolated oral candidia-
sis and should be reserved for more invasive disease.
• Individuals who face an increased risk of invasive fungal infection or suffer from
frequent recurrences may be candidates for chemoprophylaxis.
Table 6.3 Common antifungal Topical Triamcinolone-nystatin ointment for angular

regimens [3, 6–8] antifungal cheilitis
therapy Nystatin oral suspension 100,000 units/cc
Clotrimazole troches 10 mg
Clotrimazole buccal tablet 50 mg
Systemic Fluconazole 100 mg qd
antifungal Ketoconazole 200 mg qd
therapy Itraconazole 100 mg bid
Options for treating oral candidiasis are available in several forms (Table 6.3)
including rinses, suspensions, powders, creams, ointments, lozenges, capsules, and
tablets. The unique environment of salivary dilution and clearance and the action of
deglutition result in decreased therapeutic drug concentration, mandating a need for
frequent dosing. More frequent dosing schedules along with the unpalatable taste of
some formulations may lead to noncompliance and treatment failure.
Treatment choice considerations should include drug effectiveness, infection
severity, ease of administration, patient adherence, potential drug interactions, and
cost. More detailed treatment options can be reviewed in 3 and 9–12.
1 . Address underlying causes or medical conditions

2. Avoid or reduce smoking
3. Treat xerostomia/salivary gland hypofunction
4. Improve oral hygiene (chlorhexidine has some antifungal activity)
5. Use antifungal medications – topical and/or systemic therapies
References
1. Akpan A, Morgan R. Oral candidiasis. Postgrad Med J. 2002;78(922):455–9.
2. Klein RS, et al. Oral candidiasis in high-risk patients as the initial manifestation of the acquired
immunodeficiency syndrome. N Engl J Med. 1984;311(6):354–8.
3. Kragelund C, Reibel J, Pedersen AML. Management of patients with oral candidiasis.
Oral Infections and General Health. Springer International Publishing; Switzerland. 2016.
p. 137–44.
4. Lalla RV, et al. A systematic review of oral fungal infections in patients receiving cancer
therapy. Support Care Cancer. 2010;18(8):985–92.
5. Li L, Redding S, Dongari-Bagtzoglou A. Candida glabrata, an emerging oral opportunistic
pathogen. J Dent Res. 2007;86(3):204–15.
6. Lyu X, et al. Efficacy of nystatin for the treatment of oral candidiasis: a systematic review and
meta-analysis. Drug Des Dev Ther. 2016;10:1161.
7. Marable DR, et al. Oral candidiasis following steroid therapy for oral lichen planus. Oral Dis.
2016;22(2):140–7.
8. Niimi M, Firth NA, Cannon RD. Antifungal drug resistance of oral fungi. Odontology.
2010;98(1):15–25.
9. Patuwo C, et al. The changing role of HIV-associated oral candidiasis in the era of HAART. J
Calif Dent Assoc. 2015;43(2):87–92.
10. Salerno C, et al. Candida-associated denture stomatitis. Med Oral Patol Oral Cir Bucal.
2011;16(2):e139–43.
11. Samaranayake LP, Keung Leung W, Jin L. Oral mucosal fungal infections. Periodontol 2000.
2009;49:39–59.
12. Terai H, Shimahara M. Usefulness of culture test and direct examination for the diagnosis of
oral atrophic candidiasis. Int J Dermatol. 2009;48(4):371–3.
Part III
Oral Diseases of the Senses
Chemosensory Disorders
7
Joseph A. D’Ambrosio
Pearls of Wisdom
• The majority of flavor perception is derived from odorants. Thus, many
patients who present with a complaint of taste loss in actuality have smell
loss and require olfactory testing.
• Dysgeusias are typically characterized by qualities identifiable by the taste
system and should be described as either salty, sweet, sour, bitter, savory,
or possibly metallic. Any other descriptors, such as “foul” or “rancid,” are
more likely to be associated with the olfactory system and should be clas-
sified as parosmias.
7.1 Introduction
There are three chemosensory systems in the nose and mouth. Smell (olfaction) is
the ability to detect and identify odors. Taste (gustation) involves the discrimination
of five identifiable taste qualities in the mouth: salt, sweet, sour, bitter, and savory
(umami). The common chemical sense is the ability to perceive irritating stimuli in
the mouth and nose, such as the burn of a chili pepper or the tingle of ammonia.
Taste is often confused with flavor, which is the total sensory experience derived
from the smell, taste, texture, temperature, and irritating properties of food and
beverages.
J.A. D’Ambrosio, DDS, MS

Adjunct Faculty, Pima Community College, Tucson, AZ, USA
e-mail: josephadambrosio@gmail.com

DOI 10.1007/978-3-319-51508-3_7
64 J.A. D’Ambrosio
7.2.1 Smell Disorders
• Anosmia – complete loss of smell

• Hyposmia – reduced ability to smell
• Dysosmia – alteration or distortion of smell perception:
–– Parosmia (troposmia) – perception of an odor (usually unpleasant), triggered
by a stimulus
–– Phantosmia – perception of an odor, without a stimulus present (olfactory
hallucination)
7.2.2 Taste Disorders
• Ageusia – complete loss of taste

• Hypogeusia – reduced ability to taste
• Dysgeusia – alteration or distortion of taste perception. Dysgeusia may occur in
conjunction with burning mouth syndrome:
–– Parageusia – altered taste (usually unpleasant), triggered by a stimulus
–– Phantogeusia – perception of a taste, without a stimulus present (gustatory
hallucination)
7.3.1 Prevalence
• The actual prevalence of chemosensory disorders is unknown. It has been esti-

mated that more than two million Americans have some type of smell or taste
disorder. Newer estimates of the prevalence of self-reported chemosensory alter-
ations from the 2011–2012 US National Health and Nutrition Examination
Survey (NHANES) are 23% for smell and 19% for taste alterations.
• Olfactory disorders occur more frequently than taste losses, due to the anatomi-
cal distinctiveness of the olfactory system.
• Dysgeusias are intrusive and more commonly reported than actual taste losses,
which are less readily perceived.
7.3.2 Etiologic Factors
• Upper respiratory infection (usually viral)

• Sinonasal conditions:
–– Allergic rhinitis
–– Chronic rhinosinusitis
–– Nasal polyps
7 Chemosensory Disorders 65
• Head and facial trauma

• Neurodegenerative disorders:
–– Alzheimer’s disease
–– Parkinson’s disease, Parkinsonism
–– Multiple sclerosis
• Aging
• Medications:
–– Chemotherapy
–– Antimicrobials
–– Antihistamines and decongestants
–– Antidepressants
–– Antihypertensives
• Postradiation treatment
• Chronic medical conditions:
–– Cancer
–– Diabetes mellitus
–– Gastroesophageal reflux disease
–– Human immunodeficiency virus
–– Hypothyroidism
–– Renal or hepatic failure
• Psychiatric conditions
• Congenital conditions
–– Kallmann syndrome
–– Congenital anosmia
• Toxic chemical exposures
• Surgical procedures:
–– Middle ear surgery
–– Third molar extractions
• Salivary dysfunction, xerostomia
• Oral infections:
–– Candidiasis
–– Periodontal diseases
• Idiopathic
• The sense of smell involves the transport of odorant molecules through the nasal
cavity to a small patch of receptor cells in the olfactory neuroepithelium. Once
the odorants are dissolved in the mucus surface of the epithelium, receptor cells
are depolarized, and electrical signals traverse the cribriform plate to the olfac-
tory bulb. From there, neural pathways project to other parts of the brain. The
location of olfactory receptors high in the nasal cavity renders them susceptible
to changes in nasal patency and airflow patterns that potentially limit the access
of stimulus molecules. Also, the vulnerable position of olfactory nerve axons
near the cribriform plate makes them subject to tearing or severing from coup-
contrecoup forces associated with head injury.
• The neural pathways for taste are more complex. Taste receptor cells are located
primarily in taste buds in the circumvallate, foliate, and fungiform papillae of the
tongue. Additional taste receptors are found in the soft palate, pharynx, uvula,
and epiglottis. Primary sensory neurons enter the base of the taste bud and syn-
apse with taste cells. In contrast to olfaction, which is mediated by a single cra-
nial nerve (I), innervation of the taste buds is supplied by three different cranial
nerves: facial (VII), glossopharyngeal (IX), and vagus (X). The lingual branch of
the trigeminal nerve (V) also innervates the anterior tongue and provides tactile
and temperature sensation which interact with gustation to enhance flavor per-
ception. The superficial placement of taste buds makes them susceptible to direct
injury from chemicals, drugs, and viruses. Taste perception is also affected by
the quantity and composition of saliva.
• Stimulation of the common chemical sense is through branches of the trigeminal
nerve in the nose and oral cavity. The glossopharyngeal nerve provides addi-
tional sensory information.
• Most of the etiologic factors associated with chemosensory disorders can thus be
divided into two major categories:
–– Transport Dysfunction – the odorant or taste stimulus cannot make contact
with functioning olfactory neuroepithelium or taste buds.
–– Sensorineural Dysfunction – the odorant or taste stimulus cannot be processed
due to neural injury. Olfactory neurons have a slow turnover rate (30–60 days).
In contrast, taste cells have a rapid turnover rate (10–20 days) and have bilat-
eral and multiple innervation. Therefore, complete loss of taste occurs with
much less frequency than anosmia.
• Medical and dental history – documentation and differentiation of the specific

chemosensory abnormality (smell, taste, or both) including description of chief
complaint, duration, intensity, frequency, past medical history, medications, past
treatment, modifying factors, and diagnostic studies.
• Physical examination – including thorough head and neck, neurological, and
intraoral exams to rule out etiological factors noted above. A multidisciplinary
approach combining internal medicine, neurological, otorhinolaryngological,
and dental consultations may be useful.
• Chemosensory tests:
–– Odor discrimination tests determine a patient’s ability to identify a series of
common odorants such as coffee and chocolate. Commercially available
microencapsulated “scratch and sniff” tests such as the University of
Pennsylvania Smell Identification Test (UPSIT) can be self-administered by
the patient. Although the 40-item UPSIT remains the “gold standard” of
olfactory tests, briefer 3-item and 12-item variants have been developed (e.g.,
Pocket Smell Test, Quick Smell Identification Test, Brief Smell Identification
Test).
–– Odor detection threshold tests utilize progressively stronger concentrations of

an odorant such as butanol to determine the weakest dilution that a patient can
detect. Each nostril must be tested separately to determine if the smell distur-
bance is unilateral or bilateral.
–– Trigeminal function for the common chemical sense is assessed by a patient’s
ability to detect a pungent odor such as menthol.
–– Whole mouth and spatial (regional) taste tests are used to assess a patient’s
ability to identify the quality and intensity of salty, sweet, sour, and bitter
stimuli. A magnitude matching method used in specialized chemosensory
clinics requires a patient to match the relative intensities of a series of taste
solutions with sounds or weights to determine the extent of taste loss.
–– Electrogustometry delivers weak anodal electrical currents to the different
areas of gustatory innervation on the tongue in order to assess the integrity of
an individual nerve.
• Topical anesthesia or mandibular nerve blocks are useful in determining whether
the cause of a taste disorder is due to local or central factors. If the complaint
persists after the anesthetic is administered, then the source of the disorder may
originate from the central nervous system.
• Somatosensory testing with Semmes-Weinstein monofilaments can be utilized to
assess pressure detection thresholds for peripheral nerve fields in the oral cavity.
• Imaging modalities are useful for ruling out intracranial or peripheral nerve
abnormalities. The following modalities are suggested:
–– Computed tomography
–– Magnetic resonance imaging
–– Positron emission tomography
–– Single photon emission tomography.
• Laboratory tests may be necessary to diagnose underlying medical or metabolic
abnormalities.
• Improve the patient’s symptoms and quality of life

• Manage identified underlying etiologies
• Reduce the risk of unintentional weight change, malnutrition, and worsening of
concomitant medical illnesses (particularly in the elderly)
• Reduce the risk of toxic exposures (e.g., natural gas, smoke, poisons, spoiled
food)
• Treatment is highly dependent upon the specific etiologic factor.

• Prognosis for olfactory disorders is better when the patient has a reversible cause
of intranasal interference, such as nasal polyps, rhinitis, or allergies.
• Medical treatments are not as effective in restoring lost olfactory function that
results from an upper respiratory infection or head trauma.
• Factors that make improvement less likely include severity and duration of
symptoms, advanced age at onset, and smoking.
• Drug and radiation-induced dysgeusias can be reversed with cessation of the
offending agents, and other taste disorders often resolve spontaneously over time
in the absence of any treatment.
• Systemic and topically applied intranasal corticosteroids for reducing mucosal

edema and shrinking nasal polyps.
• Antibiotics, decongestants, and antihistamines for chemosensory losses due to
bacterial sinus infection and allergic rhinitis.
• Proton pump inhibitors, histamine receptor antagonists, and antacids for man-
agement of dysgeusias associated with gastroesophageal reflux disease.
• Antifungal therapy for treatment of dysgeusia associated with oral candidiasis.
• Benzodiazepines, tricyclic antidepressants, and anticonvulsants may also be
helpful for patients with dysosmias and dysgeusias. Some examples are:
–– Clonazepam 0.5–2 mg/day
–– Amitriptyline 25–100 mg/day
–– Gabapentin 300–2,000 mg/day
• The efficacy of dietary supplements such as zinc gluconate, alpha-lipoic acid,
and vitamin A for chemosensory dysfunction is inconclusive, but may be useful
for some patients.
7.7.2 Surgery
• Endoscopic and nasal sinus surgery for obstructive disorders may result in return
of normal olfactory function if more conservative approaches are unsuccessful.
7.7.3 Miscellaneous
• Management of underlying disorders such as periodontal disease and xerostomia

may improve taste function. Artificial saliva may be helpful for patients with
xerostomia.
• Masking techniques such as sugarless chewing gum, lozenges, or topical anes-
thetics may provide temporary relief for idiopathic dysgeusias.
• Baseline and repeat chemosensory testing are useful in assessing prognosis for
recovery of normal function.
• Treatment should include counseling on smoke and natural gas detection, label-
ing of food to track spoilage, and food preparation to maximize appeal and
flavor.
• Nutritional counseling is also essential, as patients may compensate for chemo-
sensory losses by overusing salts and sugars.
• Referral to a multidisciplinary taste and smell center may be necessary when
diagnosis of the specific disorder cannot be readily established.
• Patients should be reassured that chemosensory disorders are typically not life-
threatening and that recovery of normal function may take several years or may
never occur, depending upon the specific etiology.
References
1. Rawal S, Hoffman HJ, Bainbridge KE, Huedo-Medina TB, Duffy VB. Prevalence and risk fac-
tors of self-reported smell and taste alterations: results from the 2011–12 US National Health
and Nutrition Examination Survey (NHANES). Chem Senses. 2016;41:69–76.
2. Hoffman HJ, Ishii EK, Macturk RH. Age-related changes in the prevalence of smell/taste
problems among the United States adult population: results of the 1994 disability supplement
to the National Health Interview Survey (NHIS). Ann N Y Acad Sci. 1998;855:716–22.
3. Cowart BJ. Taste dysfunction: a practical guide for oral medicine. Oral Dis. 2011;17:2–6.
4. Bromley SM, Doty RL. Olfaction in dentistry. Oral Dis. 2010;16:221–32.
5. Malaty J, Malaty I. Smell and taste disorders in primary care. Am Fam Physician.
2013;88(12):852–9.
6. Bromley SM. Smell and taste disorders: a primary care approach. Am Fam Physician.
2000;61(2):427–36.
7. Cullen MM, Leopold DA. Disorders of smell and taste. Med Clin N Am. 1999;83(1):57–74.
8. Spielman AI. Chemosensory function and dysfunction. Crit Rev Oral Biol Med.
1998;9(3):267–91.
9. Doty RL. Olfaction. Annu Rev Psychol. 2001;52:423–52.
10. Mann N, Lafreniere D. Anosmia and nasal sinus disease. Otolaryngol Clin N Am.

2004;37(2):289–300.
11. Pribitkin E, Rosenthal MD, Cowart BJ. Prevalence and causes of severe taste loss in a chemo-
sensory clinic population. Ann Otol Rhinol Laryngol. 2003;112(11):971–8.
12. Comeau TB, Epstein JB, Migas C. Taste and smell dysfunction in patients receiving chemo-
therapy: a review of current knowledge. Support Care Cancer. 2001;9(8):575–80.
13. Mott AE, Grushka M, Sessle BJ. Diagnosis and management of taste disorders and burning
mouth syndrome. Dent Clin N Am. 1993;37(1):33–71.
14. Ship JA. Gustatory and olfactory considerations: examination and treatment in general prac-
tice. J Am Dent Assoc. 1993;124(6):55–62.
15. Mott AE, Leopold DA. Disorders in taste and smell. Med Clin N Am. 1991;75(6):1321–53.
Oral Malodor
8
Patricia Lenton
Pearls of Wisdom
• Chronic persistent oral malodor is often due to a combination of variables,
and a blend of treatment modalities are often required to manage breath
odor problems.
• While there are numerous products on the market that claim to effectively
treat bad breath, many products either have no published research, or very
limited published data to back up those claims. Therefore, it is challenging for
dental professionals to make evidence-based treatment recommendations.
• Bad breath treatment recommendations must be individualized for each
patient, based on their personal concerns and preferences. It is advisable to
begin with tongue and interdental cleaning and then slowly adding in sup-
plemental products based on evidence and patient preferences.
• Product use may require 2–3 weeks of consistent application to determine
efficacy.
• Future research of bad breath treatment regimens may provide a better
understanding of the factors that contribute to breath odor production and
ways in which to interrupt the production of the volatile sulfur compounds
known to be the principle components of bad breath.
8.1 Introduction
Oral malodor, also known as bad breath or halitosis, refers to unpleasant odors that
come from the mouth. Most bad breath is considered to be transient in nature, for
example, morning breath. However, it has been estimated that up to 25% of the
population suffer from bad breath on a regular basis in spite of having good physical
P. Lenton, BSDH, MA, CCRP

Oral Health Clinical Research Clinic, School of Dentistry, University of Minnesota,
e-mail: lento001@umn.edu
DOI 10.1007/978-3-319-51508-3_8
72 P. Lenton
and oral health and after the elimination of offensive foods and beverages. Having
chronic offensive breath odor can be detrimental to one’s self-image and confi-
dence, causing social, emotional, and psychological anxiety.
Most breath odor experts agree that about 90% of breath odor originates within
the mouth. Since the majority of breath odors have an oral origin, the dental office
is the most logical place for patients to seek advice and treatment. When patients
look to dental professionals for expert advice, it is important that we are prepared to
explain the causes of oral malodors, that we are able to assess our patients’ breath,
and that we can provide recommendations for helping patients manage their breath
odor. It is also important for dental professionals to recognize when breath odor
might have an extraoral origin because this could signal a potentially serious disease
and warrant a referral to a health professional (Tangerman, 2012).
The following information is provided to help dental professionals assess the
source of their patients’ oral malodors and assist their patients in reducing and man-
aging their breath odor.
Patients with breath odor and/or breath odor concerns present with varying character-
istics. Due to the phenomena of adaptation and habituation, it is difficult for a person
to assess their own breath odor or other bodily odors. For this reason, some people
have bad breath but are unaware of it. Other patients have bad breath and are aware of
it, often because people who are significant in their life have told them so. Still others
may complain of bad breath even though others cannot detect it. Many of these afore-
mentioned patients can be reassured and educated in methods to assess and manage
their breath odor. However, there is a small segment of the population that can develop
a delusional or an exaggerated perception about some aspect of their being, in this
case, having bad breath that they believe warrants extreme measures to fix. This is
known as a body dysmorphic disorder (BDD) and in the case of breath is character-
ized by an obsessive preoccupation about having extremely offensive breath odor.
The term most often used by dental professionals to describe these persons is halito-
phobia or olfactory reference syndrome (ORS). Persons with halitophobia are
extremely difficult to convince that they don’t have bad breath. Treating ORS patients
in the dental office is extremely challenging. Fortunately, the overwhelming majority
of breath odor concerns can be successfully managed in the general dental practice.
Persons with genuine halitosis need to be evaluated, beginning with a thorough
medical history to determine any medications that they are taking and also to find
out if they have any medical conditions associated with breath odor.
Breath odor results from the bacterial breakdown by gram-negative anaerobic bac-
teria, particularly those residing on the posterior dorsum of the tongue, of sulfur-
containing amino acids. The released sulfurs volatize and are expelled from the
8 Oral Malodor 73
mouth. The principle volatile sulfur compounds (VSCs) associated with intraoral
breath odor are hydrogen sulfide (H2S), methyl mercaptan (CH3SH), and to a lesser
degree, dimethyl sulfide (CH3)2S.
It is widely accepted that 80 to 90% of all bad breath has an oral origin, and of
that, 80 to 90% is produced on the posterior third of the tongue. Other dental prob-
lems, such as periodontal disease, over-hanging dental restorations, dry mouth, and
tonsilar crypts can also contribute to the generating these offensive gases.
The remaining 10% of breath odor can be attributed to non-oral (extraoral)
sources. Extraoral halitosis is classified as being either non-blood borne such as
halitosis from the sinuses and/or respiratory tract infection or blood-borne halitosis
that can include certain systemic disorders. The majority of extraoral halitosis is
from blood-borne causes and is associated with the VSC, dimethyl sulfide [(CH3)2S].
When assessing breath odor, it is important to distinguish between intra- and extra-
oral halitosis because blood-borne halitosis can be indicative of a serious disease.
The easiest way to determine if the odor has an oral origin is to compare the odor
coming from the mouth with the odor level that comes from the nostrils. Therefore,
once it has been determined that an individual’s expelled breath has an odor, you
would then assess the odor level when they expel air through their nostrils. If the
odor remains, and at the same intensity, as the odor detected from the mouth, then
you would refer the affected patient for a medical consultation.
8.4.1 Oral Pathological Etiology (90% of Chronic Bad Breath)
1. Tongue coating on the dorsum of the tongue (80% of oral malodor):

• Bacterial-laden tongue coating consisting of anaerobic bacteria.
• Degradation of sulfur-containing amino acids found in oral fluids, tissue, and
food debris produces volatile sulfur compounds (VSCs), primarily hydrogen
sulfide and methyl mercaptan resulting in pungent rotten egg smell.
• Thorough tongue scraping starting in the area of the circumvallate papilla and
scraping in a forward motion seven to ten times until tongue coating appears
clear and the brushing of all other oral structures and interdental cleaning will
reduce VSCs and eliminate most oral malodor for up to 3 h.
• The use of antibacterial, zinc-containing, and/or oxygenating products, twice
daily, have been shown to reduce the production of VSCs and breath odor
levels.
• Regular meal eating and good hydration can reduce VSCs for up to 2 h.
2. Periodontitis:
• Periodontal pathogens (P. gingivalis, T. denticola, B. forsythus) produce
VSCs, primarily methyl mercaptan that has a pungent spoiled cabbage smell.
• Increased tongue coating is associated with periodontal disease.
• Generalized periodontitis with moderate to severe bone loss is needed to pro-
duce and release adequate concentrations of VSCs from the sulcus to achieve
detectable, offensive breath odor.
74 P. Lenton
• Therapeutic periodontal treatments (scaling/root planing, referral for surgical

interventions, and thorough daily home care, including thorough tongue
scraping) generally reduces/eliminates odor.
• Patients with a breath concern often choose to incorporate mouth rinsing as part
of their oral hygiene regimen for reassurance. The use of oral rinses also can
assist in reducing the incidence of experiencing the report of having a bad taste
that can occur with or without periodontal disease.
3. Unclean dentures and partials:
• If plaque and calculus are present, clean denture/partials using a brush and
water only and place them into a sealed plastic bag for 5–10 min. Smell bag
for odor quality and intensity.
• Compare mouth odor, with dentures removed, to odor of the bagged dentures.
Stronger odor in bag is indicative of denture odor origin.
• If candida is present, oral odor will have a sweetish acid quality, and appropri-
ate antifungal treatment will be required.
• Daily denture cleaning and soaking with over-the-counter effervescent tablets
will generally control most denture/appliance odor.
• Patient should remove denture(s) out overnight to prevent bacterial accumulation.
• For persistent odor, appliances can be soaked in Peridex for 10–15 min.
Prolonged soaking in Peridex may cause staining. Do not use bleach or per-
oxide due to bleaching and corrosive nature.
4. Postnasal drip:
• A significant amount of this mucous does end up in the mouth and provides a
substantial amount of cysteine and methionine (amino acid substrate) for bac-
terial putrefaction.
• Patient will have the distinctive odor quality of sulfur (rotten eggs).
• Odor is often intermittent and with varying intensity. Patient may be unaware
of the problem since it is difficult to self-assess.
• Thorough tongue scraping and gargling with a zinc and/or antimicrobial
mouth rinse often eliminates most of the offending problem; however, if per-
sistent, the patient can use antimicrobial sprays to reach those areas that can-
not be brushed or scraped, such as the throat and tonsils.
• Patients who regularly use antihistamines, inhalers, or other medications
known to result in dry mouth should maintain meticulous home care and
drink fluids to improved hydration, and prevent reduced salivary flow, which
intensify the level of odiferous compounds into oral cavity.
• Some patients benefit from use of saline nasal sprays and/or the use of netti
pots. Please note, if patients want to use a Netti pot they should be encouraged
to use either distilled water, or, water taht has been boiled and allowed to cool.
5. ANUG:
• Overwhelmingly pungent fetid odor of rotting hay or sulfides associated with
necrosis of gingival tissues.
• Gingival debridement and antibiotic therapy will eliminate odor.
• Daily and routine professional oral care needed to maintain oral health.
6. Tonsiloliths:
• Calcified material attached to tonsils with a pungent rotten cabbage smell.
8 Oral Malodor 75
• Patient is often aware of the calcifications and is often very self-conscious of

the possibility of offending others.
• Generally odor can only be detected when placed in close proximity of the
nose. Others generally cannot smell a person’s tonsiloliths when talking at a
social-distance apart.
7. Dental abscesses and localized infections:
• Patients with localized infections will often complain of having a bad taste
(sour or bitter) in their mouth. When patients perceive a bad taste in their
mouth they often equate this with having a breath odor problem when none
exists.
• Patient would need to have a significant abscess or generalized oral infections
before breath odor would be noticeable to others.
• Off tastes (a.k.a. after or bad tastes) are usually the result of medications,
sinus drainage, xerostomia, dental infections, and bacterial putrefaction
around defective restorations.
• If the off taste is due to an infection, treatment of the localized infection
together with the use of an antimicrobial mouth rinse will often eliminate off
taste sensations and eliminate complaint of bad breath.
8.4.2 O
ral Physiological Factors (Not Causal But Contributing
Factors to Oral Malodors)
1. Morning breath:
• Reduced salivary flow during sleep favors bacterial putrefaction and the dry-
ness intensifies odor levels.
• Unclean mouth gives patient perception of offensive odor.
• Transient and will disappear after oral stimulation (talking, eating, etc.).
2. Xerostomia caused by medications or salivary dysfunction:
• Reduction of salivary flow rate and stagnation of saliva contribute to bacterial
shift that can increase oral malodor formation (Kleinberg and Westbay).
• Alkaline environment is also associated in oral malodor production.
• Lack of wetting of mucosa increases release of offending compounds into the
oral air.
• Patients suffering from reduced salivary flow should frequently drink and
rinse oral cavity with water for continued hydration of the oral mucosa.
• Eating regularly will lower pH, provide some mechanical debridement to help
reduce bacterial growth on tongue, and also stimulate salivary flow. Fasting/
hunger can has also been associated with oral malodor due to dehydration.
• Frequent oral stimulation and use of artificial saliva may be helpful.
3. Large carious lesions and or defective restorations:
• Trapping of food debris by generalized poor or lack of dental care usually
does not produce sufficient level of odor to offend others.
• Patient may experience bad taste and perceives odor exists.
• Professional dental care and thorough oral home care often eliminates patients
concerns.
76 P. Lenton
8.4.3 Non-pathological and Nonphysiological Factors (10%)
Halitosis can be caused by the absorption of malodorous compounds through the

digestive system and transferred and released through the respiratory system or can
be a symptom of a late stage pathogeneses (e.g., cancer, kidney failure). Professional
or home care will not eliminate problem. Patient will need to be referred to physi-
cian for diagnosis and treatment.
1. Pulmonary abscesses, pneumonia, and bronchial conditions:

• Pungent sewer-like odor (diseased tissues) for proliferation of anaerobic bac-
teria with tissue destruction or decaying blood quality
• Often associated with other symptoms (cough, difficulty breathing, etc.)
• Referral for medical treatment of infection or condition
2. Sinusitis and nasopharyngeal infections:
• Nasal malodor usually has a slightly cheesy odor characteristic.
• Often it is transient lasting 7–10 days.
• Chronic persistent problem needs referral to physician.
• A nasal odor that only occurs during the morning may be indicative of a con-
centrated nasal mucous accumulation during sleep. Odor may last for 1–2 h
until mucous has been discharged. The use of nasal sprays or drinking hot
liquids can be helpful in eliminating the mucus buildup.
3. Diet: strong spicy foods (garlic, curry, onions, etc.) and alcohol consumption:
• Odorant will have a specific quality similar to offending food/beverage.
• High protein low carbohydrate can induce ketosis with a characteristic ace-
tone smell.
• Large quantities of protein supplements above recommendation can produce
distinctive musty and stale-like odor and bad taste.
• Can last for up to 36 h; however, odor will typically disappear after absti-
nence, and the compounds are metabolized and released into the lungs.
• Frequent use of flavored rinses, gums, mints, and sprays will mask odor.
4. Medications:
• Disulfiram (alcoholism) metabolized to carbon disulfide (slight fecal odor).
• Dimethyl sulfoxide (muscle pain) and cysteamine (nephropathic cystinosis)
metabolized to dimethyl sulfide (garlic odor).
• Frequent use of flavored rinses, gums, mints, and sprays reduces odor inten-
sity by masking odorant.
• Medications can alter taste sensations and is not associated with malodor.
• Referral to physician for evaluation of prescription change or if odor percep-
tion has psychological concerns.
5. Tobacco use – distinctive nicotine odorant quality from lungs:
• Occasional smoker – Frequent use of flavored rinses, gums, mints, and sprays
will mask odor until gone (5–8 h).
• Heavy smoker – Frequent use of flavored rinses, gums, mints, and sprays will
not completely mask odor. Complete abstinence is required for several weeks
to remove offending nicotine tars in lungs.
8 Oral Malodor 77
6. Metabolic disorders will have distinctive odor quality:

• Trimethylaminuria (TMA) enzyme insufficiency to metabolize trimethylamine.
Distinctive fishy amine odor in urine, sweat, and breath with a constant presence
of odor 24/7. Referral to primary physician for evaluation is recommended.
• Hypermethioninemia involves high levels of methionine with an overwhelm-
ingly sweet odor in urine and breath. Referral to primary physician for evalu-
ation is recommended.
7. Systemic conditions/diseases will have characteristic odor quality:
• Diabetes, incomplete carbohydrate metabolism (ketoacidosis):
–– Distinctive acetone scent in breath (rotting apples)
–– Usually intermittent unless uncontrolled
–– Referral to primary physician for evaluation
• Liver failure/cirrhosis, shunting of portal blood around the liver:
–– Distinctive musty garlic-like odor in breath and blood
• Kidney disease/failure:
–– Accumulation of dimethylamine and trimethylamine
–– Distinctive stale urine/fishlike odor in breath, blood, and urine
• Gastric reflux, H. pylori, or stomach conditions:
–– Odor expelled during intermittent belching or vomiting.
–– Patient may complain of heartburn.
–– Heavy acidic sour odor.
–– Rinsing with water or product use for foul taste.
–– Referral to primary physician for evaluation.
8.4.4 Undetectable Malodor (Oral and Non-oral)
1. Halitophobia or olfactory reference syndrome – Clinician should suspect the

patient has an exaggerated fear they suffer from bad breath if:
• Clinician cannot smell any odor at three to four separate odor evaluation
appointments.
• Patient cannot provide a confirmation from a confidant stating they have
personally noticed mouth odor from the patient.
• Objective instruments do not record detectable levels VSCs or microbes.
• Patient believes they can smell the odor and indicates it lasts all day.
• Patient indicates that it interferes with social life and ability to work, and they
avoid interacting with others.
• Patient practices concealment by frequent use of gum chewing, eating mints,
toothbrushing, keeps at safe distance, and/or covers mouth when talking to
others.
• Patient has sought treatment and evaluation from several other health profes-
sionals (ENT, gastroenterologist, etc.).
78 P. Lenton
• Patient shows signs of anxiety and depression and/or express unhappiness

with life overall.
2. Provide patient with reassurance that their perceived odor is not offensive:
• Give patient permission to talk to you freely about this embarrassing topic
and their concerns.
• Encourage discussion and give information about the causes of malodor for-
mation and perceptions others may have about bad breath.
3. Provide strategies for self-assessment:
• Self-assessment techniques (wrist lick, spoon, syringe collection test).
• Encourage identification of a confidant to help patient monitor changes in
odor over time (trusted friend, family member, co-worker).
4. Consider referral for psychological assessment and counseling if suspicious of
body dysmorphic dysfunction (BDD), which is a subclass of obsessive-
compulsive disorders. Antipsychotic chlorpromazine and tricyclic antidepres-
sants have had some success in treating BDD in malodor patients.
8.5.1 Clinical Examination
Patient needs to present having prepared for odor evaluation by refraining from:
• Taking antibiotics at least for 1 month prior to examination.

• Eating strong spicy foods for 48 h before examination.
• Eating or drinking flavored beverages for 6–8 h before examination. Water is
permitted up to 2 h before examination.
• Wearing scented personal care products (colognes, hair spray, aftershave, etc.)
on examination day.
• Using oral care products for 10–12 h before evaluation.
8.5.2 Subjective Sensory Evaluation Methods
The human nose provides the best test to determine if a patient has a bad breath
problem; therefore, it is important to simply smell and assess their breath. It is
important that the person who is conducting the evaluation has a good sense of
smell and that they are not overly sensitive to malodors so that they are able to accu-
rately evaluate the breath odor quality and intensity. This is a good protocol for
assessing a person’s breath:
1. Patient keeps mouth closed for 2 min and then repeats “Pat’s Puppy” several
times while the practitioner uses an index card to waft the breath toward their
own nose and directly sniffs the breath for odor intensity and quality. (Pronouncing
words that begin with the letter “P” helps to project the breath.)
8 Oral Malodor 79
2. Patient closes their mouth and exhales through their nasal passages while the
practitioner evaluates nostril breath for intensity and quality and compares to the
odor intensity of the patient’s oral breath.
3. Oral origin – If odor is stronger from mouth than nasal passages then:
• Comprehensive dental examination for oral pathology is performed (e.g.,
periodontal disease, plaque retentive restorations and large carious lesions,
ulcerations and acute oral infections).
• Assess cleanliness of dentures and partials. Place in plastic bag for 10 min
then smell bag odor. Clean appliances with brush and tap water and place in
plastic bag for another 10 min. Open bag and smell for odor. Compare odor
form oral cavity to odor in bag.
• Evaluate levels of gingival plaque and bacterial tongue coating. Scrape poste-
rior dorsum with plastic spoon and smell plaque accumulation for odor for
similarity to mouth odor.
• Assess salivary flow. Saliva and soft tissues may have the capability to store
large quantities of VSCs.
• Characteristic oral odor will be rotten egg (sulfur) or sweet fecal (mercaptans).
4. Non-oral origin – If odor emitted from the nasal passages is equal to or stronger
than the odor from the oral cavity, then a systemic condition should be considered:
• Obtain a thorough medical history and review for possible metabolic distur-
bances or diseases.
• Frequency and types of prescription and OTC medications used.
• Frequency of acute respiratory infections or conditions.
• Dietary evaluation for characteristic food odors and dramatic dietary changes
for metabolic processes (Atkins, vegetarian high in sulfur, hunger/starvation,
dehydration).
• Medications and systemic conditions will have a characteristic odor quality
(fishy, acetone, ammonia, etc.) and is generally different from typical bacte-
rial plaque odor.
5. History of odor onset and intensity:
• Equal intensity from the nose and mouth – systemic origin and will usually
have a distinctive quality.
• Quick onset and strong intensity – acute infection in respiratory system.
• Intermittent odor – gastrointestinal, habits, and will have characteristic qual-
ity (garlic, onions, alcohol).
• Rapid onset and progressively intensifying breath malodor is suggestive of an
infective process, possibly secondary to carcinomas or other localized pathol-
ogies in the airway.
• Slow gradual onset with varying intensity with periodic absence – chronic
condition and/or disease progression.
• Quick onset or periodic and regular occurrence – gastric conditions, hormonal
(puberty, menses), and/or routine medication use.
• Regular daily occurrence associated with medication, poor eating habits, and
lack of fluid intake.
• Time of onset and relationship to major changes in life – stress, social, and
psychological events.
80 P. Lenton
• Duration of problem – Patient states that the odor is every day, 24 h day, and
extremely offensive patient is probably halitophobic.
6. Personal practice questionnaire:
• Patient’s perception of problem – intensity, duration, starting date, taste.
• Dietary practices – type and amount of fluids and foods, special diets.
• Habits – smoking, alcohol.
• Frequency of use of oral care products.
• Illness and attitude questions to identify anxiety, phobias, and compulsive
activities.
• How did patient determine they have a malodor problem? Third-party
verification.
• What is the patient’s belief as of the cause of their malodor?
• Previous examinations by health professionals and their findings and recom-
mendations. What is the patient’s perception of these findings?
8.5.3 Objective Evaluation Instruments
In addition to subjective assessment of breath odor levels, it is ideal if you also have
an “objective” method for assessing breath odor. This is especially true if you plan
to offer ongoing breath odor assessment and treatment in your practice.
1. Halimeter® is used for evaluating nasal and oral breath:

• Only measures total sulfur level; typically, over 100 parts per billion (ppb)
indicates offensive odor level.
• Correlated to sensory odor judges.
• Requires large sample volume.
• Sensor measures total VSCs and is more sensitive to hydrogen sulfide than
methyl mercaptan. Sensor easily contaminates with alcohol- and/or essential
oil-containing products. Need to follow the manufacturer’s instruction to wait
for a defined period of time following usage of such rinses to avoid contami-
nating the sensor.
• Fast, portable, easy to use, and good for measuring improvement over time.
2. OralChroma™ is used for evaluating nasal and oral breath:
• Measures hydrogen sulfide, methyl mercaptan, and dimethyl sulfide individu-
ally. (If over 80 ppb, it indicates offensive odor.)
• Requires less than 5 ml of sample and 8 min per analysis time.
• Correlated to sensory odor judges.
• Portable, easy to use, and works well to measure improvement over time.
• Expensive and requires some training for use.
3. Gas chromatography used for evaluating nasal and oral breath (gold standard).
This analytical method is usually reserved for large institutions due to the cost
and specialized technical skills involved in using the equipment:
• Can identify specific compounds in addition to VSCs.
• Requires little time and small sample volumes.
• Excellent sensitivity, specificity, and reliability.
8 Oral Malodor 81
• Expensive and needs trained personnel.

4. BANA test (benzoyl-DL-arginine-2-napthylamide synthetic peptide):
• Analysis for microbes producing trypsin-like enzyme T. denticola, P. gingiva-
lis, and B. forsythus associated with periodontal disease and oral malodor
• Small chair side incubator with 5 min analysis time
• Correlates well sensory odor judges
• Can be used before and after treatment to visually show the patient the differ-
ences following treatment
Given that the majority of bad breath has an oral origin and that the majority of
breath odor emitted from the mouth results from the bacterial coating on the poste-
rior dorsum surface of the tongue, the most important treatment recommendation is
for patients to mechanically clean their tongue. Some oral malodor researchers have
raised concerns about patients becoming overzealous about cleaning their tongue
and scraping too hard so that they actually traumatize the tongue’s surface. For this
reason, it is important to give detailed oral hygiene instructions to patients for whom
tongue cleaning is recommended.
As mentioned previously, fully comprehensive oral hygiene instructions are key to

patients for whom tongue cleaning is recommended.
In addition to mechanical debridement, chemotherapeutic methods are often
employed. The following methods outline several options:
8.7.1 Mechanical Debridement
1. Tongue cleaning with scrapers:

• Tongue scrapers come in a variety of shapes and sizes.
• Smaller working ends allow for better access to the most posterior regions of
the tongue.
• If gagging is a problem, have patient rinse with very cold water before scrap-
ing or pant while scraping the tongue.
• To prevent curling of tongue, patient can hold end with clean cloth to flatten
tongue during cleaning.
• Starting at the most posterior region of the tongue dorsum, the scraper is
drawn to the anterior while maintaining a gentle pressure. Pressing hard may
damage tongue surface.
• Tongue should be scraped seven to ten times cleaning the entire dorsal surface.
2. Tongue cleaning with brushes
• Tongue brushes come in a variety of shapes and sizes.
82 P. Lenton
• Brushes are generally used after scraping to apply antimicrobial agents to the
tongue surface.
• Use short circular motions with light pressure to work chemical agent into the
fissures and between the tongue papillae.
• Scraping of residual agent is required after application, and refraining from
rinsing after scraping will allow the chemical agent prolonged access to
offending compounds and bacteria.
8.7.2 Localized Chemical/Antibacterial Methods
Mouth rinsing is often used as a chemical approach to treat chronic and persistent
oral malodor cases. Mouth rinse efficacy must balance the elimination/reduction of
the pathogenic bacteria while maintaining the balance of the normal oral flora and
preventing an overgrowth of opportunistic pathogens. If rinses are not used in con-
junction with oral debridement, their effect will only be temporary since they are
unable to penetrate thick layers of bacterial plaque and mucus.
1. Antimicrobial agents
(a) Chlorhexidine – can be used for a defined period of time:
• Very effective broad-spectrum bactericidal agent.
• Does reduce anaerobic bacteria on the tongue dorsum.
• Substantivity increases efficacy.
• Long-term use is not recommended due to adverse effects of staining and
altered taste.
(b) Peroxides:
• Oxygenating mechanisms are effective against anaerobic microbes.
• Able to oxidize and reduce sulfur compounds.
• Use of full-strength hydrogen peroxide is not recommended due to pos-
sible soft tissue effects. There are peroxide products on the market that
use an attenuated level of hydrogen peroxide.
(c) Zinc-containing products:
• Zinc ions bind to protein receptors on the surface of the bacteria prohibit-
ing proteins from binding and preventing protein metabolism, therefore
preventing production of new VSCs.
• Zinc ion also binds to sulfur radicals inhibiting the expression of the VSCs.
• Zinc rinses (in chloride, citrate, or acetate form) used twice daily have
been found to reduce oral VSC concentrations for greater than 3 h.
• Zinc-based products usually have strong flavoring agents to mask the zinc
taste.
• Mainly used in rinses but also found in tongue-cleaning gels, chewing
gums, and lozenges.
(d) Chlorine dioxide – most widely promoted rinse for the control of oral
malodor:
8 Oral Malodor 83
• Chlorine dioxide (ClO2) is a strong oxidizing agent that has a high affin-
ity for sulfur-containing compounds and can oxidize some amines and
phenols.
• Has affinity for cell surfaces and concentrates in plaque and soft tissues.
• Bacterial effect may be interference with protein synthesis and alterations
in cell wall permeability.
• ClO2 has a short shelf life therefore needs to be mixed just before using.
Sodium chlorite is stabilized chlorine dioxide and has a longer shelf life
but less ClO2 availability in the solution.
(e) Cetylpyridinium chloride (CPC) in many OTC rinses:
• Cationic quaternary ammonium compound with antiseptic
• In vitro as effective as CHX however not as effective in vivo which is due
to low substantivity
(f) Triclosan (2,4,4′-trichloro-2′-hydroxydiphenyl ether):
• Broad-spectrum nonionic lipid soluble antimicrobial agent.
• Effective against most types of oral cavity bacteria.
• A mouth rinse system combining zinc and triclosan has been shown to
have a cumulative effect, with the reduction of malodor increasing with
the duration of the product use.
• Formulation mainly in toothpastes but also found in some rinses. (Note:
effective September, 2017, the United States Food & Drug Administration
(FDA) has banned the use of Triclosan in rinses and other products due to
a lack of evidence of efficacy).
A flowchart is displayed in Fig. 8.1, which will help guide clinicians to manage
halitosis.
• The primary goal is to assist the patient in managing their breath odor level so
that is below the level of detection by the human nose.
• Improving patients’ quality of life, especially the psychosocial aspects, is of
utmost importance.
• Reassurance that everyone suffers from bad breath and it is often not as intense
as one imagines is an important concept to explain.
• Provide patient with strategies for determination of oral malodor presence and
self-assessment of odor intensity are important.
• Treatment sequence:
–– Dietary counseling is an important consideration, especially if the patient eats
abundant sulfur-producing foods (e.g., onions, garlic, horseradish, etc.).
–– Must include daily debridement of the tongue. If tongue cleaning reduces
odor but there is some detectable offensiveness, then chemotherapeutic agents
should be added to the treatment regimen.
84 P. Lenton
Flowchart in a Halitosis Practice
Before appointment Medical questionnaire

Halitosis questionnaire
Instructions for 1st visit
1st appointment Halitosis history

Medical anamnesis
Halitosis anamnesis
Clinical examination
Halitosis examination
-Organoleptic scores
VSC determination:
-Sulphide monitors+Gas chromatography
Diagnosis
Temporary halitosis
Morning bad breath
Genuine halitosis
Extra-oral Intra-oral Pseudo

halitosis halitosis halitosis
Physiological halitosis Pathological halitosis
Tongue Periodontium Others
Referral ANUG Xerostomia Referral

ANUP Caries
Tongue
Gingivitis Menstrual
physician coating cycle? physician
specialist Periodontitis specialist
Stress?
Therapy
ENT Halitophobia
Internal medicine
Adjustment of therapy Psychiatrist
Fig. 8.1 Flowchart for halitosis management (Permission to reproduce needs to be requested to
Winkel et al. [16].)
8 Oral Malodor 85
–– Products containing zinc, chlorine dioxide, or cetylpyridinium chloride have

been shown to be helpful.
–– Product must reach source of odor and remain long enough to have an effect.
Therefore, sprays may be indicated for the throat and far posterior regions of the
tongue, tongue-cleaning gels for thick tongue coatings and rinses, and lozenges
and gums for reduced salivary flow which may be beneficial for odor control.
References
1. Furne J, Majerus G, Lenton P, Springfield J, Levitt D, Levitt M. Comparison of volatile
sulfur compounds measured with a sulfide detector vs gas chromatography. J Dent Res.
2002;81(2):140–3.
2. Kawaguchi Y. Psychological management of halitosis. In: Yaegaki K, editor. Clinical guide-
lines for halitosis. Tokyo: Quintessence Publishing; 2000. p. 87–96.
3. Kleinberg I, Westbay G. Salivary and metabolic factors involved in oral malodor formation.
J Perinatol. 1992;63:768–75.
4. Lenton P, Majerus G, Bakdash B. Counseling and treating bad breath patients: a step-by-step
approach. J Contemp Dent Pract. 2001;2(2):1–13.
5. Morita M, Wang HL. Association between oral malodor and adult periodontitis: a review.
J Clin Periodontol. 2001;28:813–9.
6. Nakano Y, Yoshimura M, Koga T. Correlation between oral malodor and periodontal bacteria.
Microbes Infect. 2002;4:679–83.
7. Quirynan M, Mongardini C, van Steenberghe D. The effect of a 1-stage full-mouth disinfec-
tion on oral malodor and microbial colonization of the tongue in periodontitis patients. A pilot
study. J Periodontol. 1998;69:374–82.
8. Seemann, Rainer, et al. “Effectiveness of mechanical tongue cleaning on oral levels of volatile
sulfur compounds.” The Journal of the American Dental Association 132.9 (2001):
1263–1267.
9. Suarez F, Jurne J, Springfield J, Levitt M. Morning breath odor: influence of treatments on
sulfur gases. J Dent Res. 2000;79(10):1773–7.
10. Tangerman A. Halitosis in medicine: a review. Int Dent J. 2002;52(3):201–6.
11. Van Steenberghe D. Breath malodor. Curr Opin Periodontol. 1997;4:137–43.
12. Winkel E, Roldan S, Winkelhoff A, Herrera D, Sanz M. Clinical effects of a new mouthrinse
containing chlorhexidine, cetylpyridinium chloride and zinc-lactate on oral halitosis. J Clin
Periodontol. 2003;30:300–6.
13. Yaegaki K, Coil JM. Tongue brushing and mouth rinsing as basic treatment measures for hali-
tosis. Int Dent J. 2002;52(3):192–6.
14. Tangerman A, et al. Halitosis and Helicobacter pylori infection. J Breath Res. 2012;6(1):017102.
15. Tangerman A, Winkel EG. Volatile sulfur compounds as the cause of bad breath: a review.
Phosphorus Sulfur Silicon Relat Elem. 2013;188(4):396–402.
16. Seemann R, Conceicao MD, Filippi A, Greenman J, Lenton P, Nachnani S, Quirynen M,
Roldan S, Schulze H, Sterer N, Tangerman A, Winkel EG, Yaegaki K, Rosenberg M. Halitosis
management by the general dental practitioner—results of an international consensus work-
shop at BREATH ANALYSIS Summit 2013—International Conference of Breath Research,
9th of June 2013—Saarbrücken/Wallerfangen, Germany. J Breath Res. 2014;8(1):017101.
Part IV
Salivary Gland Dysfunctions
Salivary Gland Dysfunction
and Xerostomia 9
Mahvash Navazesh
Pearls of Wisdom
• Saliva plays an important role in oral and systemic health.
• Dry mouth or xerostomia is a common complaint among patients of differ-
ent ages in general and among geriatric and medically complex patients in
particular.
• Salivary gland disorders are caused by a variety of etiologic factors.
• Salivary gland dysfunction may lead to irreversible intraoral hard and soft
tissue changes and ultimately may reduce the quality of life.
• Oral healthcare providers play a significant role in risk assessment, early
detection, management, and prevention of salivary gland disorders. These
are essential for maintaining a proper oral and systemic health in this
patient population.
9.1 Introduction
Saliva plays a significant role in oral and systemic health. The major functions of
saliva include, but are not limited to, lubrication, intraoral hard and soft tissue pro-
tection, remineralization of teeth, and digestion.
Qualitative and quantitative changes associated with salivary gland disorders
could affect the quality of life of an individual. Recurrent dental caries and oral
fungal infection are the most common complications associated with chronic sali-
vary gland dysfunction.
M. Navazesh, DMD
Division of Diagnostic Sciences, Herman Ostrow School of Dentistry,
University of Southern California, Los Angeles, CA, USA
e-mail: navazesh@usc.edu

DOI 10.1007/978-3-319-51508-3_9
90 M. Navazesh
Saliva contains more than 2,000 proteins that are involved in different biologic
functions to maintain oral homeostasis. Salivary biomarkers have received signifi-
cant recognition by different scholars in recent years for their potentials in the
detection of early stages of oral and systemic diseases.
Firstly, it is important to define these two key concepts:
• Xerostomia: the subjective complaint of dry mouth.

• Salivary gland dysfunction: objective evidence of alterations (qualitative and/or
quantitative) in saliva output. Dysfunction may include a decrease (hypofunc-
tion) or an increase (hyperfunction) of the saliva output.
9.2.1 Symptoms
• Asymptomatic (no dry mouth complaint)

• Difficulty chewing, speaking, swallowing, wearing removable intraoral prostheses
• Dry, sore, or burning symptoms in the eyes, mouth, tongue, lips, throat, nose
• Bad breath
• Taste abnormalities including salty, metallic, bitter sensations (dysgeusia)
• Facial swelling or pain, ear pain
• Frequent need to sip water with food or awakening at nighttime with dry mouth
• Drooling due to excessive salivation (sialorrhoea)
9.2.2 Signs
• Salivary gland enlargement

• Lack of saliva upon palpation of salivary glands
• Atrophic mucosal changes involving orifices of major salivary glands
• Blood or pus contaminated saliva upon palpation of major glands
• Dry, inflamed intraoral mucosa
• Inflamed, lobulated tongue mucosa
• Rampant dental caries
• Recurrent dental caries
• Extensive restorative experience
• Recurrent oral fungal infection
9.3.1 Etiological Factors
• Genetic disorder (salivary gland aplasia).

• Inflammation (sialadenitis) is the most common cause of salivary gland dysfunc-
tion. Most common causes of sialadenitis:
9 Salivary Gland Dysfunction and Xerostomia 91
–– Sialoliths
–– Bacterial and viral infections
–– Polypharmacy
• Neoplasm (adenoma, carcinoma type).
• Noninflammatory, nonneoplastic enlargement (sialadenosis).
9.3.2 Prevalence
The prevalence of salivary gland dysfunction and xerostomia varies in different

population and age groups based on ethnicity, gender, medical conditions, medica-
tions, severity of the medical conditions, and type, dosage, and frequency of medi-
cation usage.
Salivary gland dysfunction and xerostomia may be transient or permanent, acute or

chronic in nature based on the etiologic factor(s). Common systemic conditions
associated with salivary gland dysfunction are:
• Autoimmune (Sjogren’s syndrome, scleroderma, lupus erythematous)

• Cardiovascular (hypertension)
• Endocrine (hypothyroidism, unstable diabetes)
• Neurologic (Alzheimer’s disease)
• Psychiatric (depression, anxiety disorders)
• Infectious (HIV, HCV, paramyxovirus)
Salivary gland function altered by autoimmune diseases is often irreversible in

nature. Sjogren’s syndrome affects mostly women and involves the exocrine glands’
function leading to dry mouth and dry eyes. The lymphocytic infiltration of normal
tissue by the disease process is permanent in nature and leads to major clinical com-
plications if not addressed in a timely manner.
Common pharmacotherapeutic approaches associated with complications of
salivary gland dysfunction:
• Irradiation to the head and neck regions

• Chemotherapy
• Anticholinergic medications
• Selected antiretroviral medications, sedatives, analgesics, antihypertensives,
anticonvulsives, cytotoxics, and antidepressants
Radiation-induced salivary gland damage is often permanent in nature in about 40%

of patients. New treatment modalities such as intensity-modulated radiation therapy
(IMRT) and gland-sparing techniques may help present such irreversible damage.
The severity and reversibility of the salivary gland changes caused by pharmaco-
therapeutic agents vary significantly. However, inflammatory changes caused by
92 M. Navazesh
most other categories of drugs are transient and could be reversible if the medica-
tions are discontinued or salivary changes are compensated for in a timely manner.
The risk assessment and diagnostic workup is key when a patient complains of dry
mouth and/or positively answers the dry mouth questionnaire. In Fig. 9.1, a flow-
chart is displayed to better understand how to evaluate and manage xerostomia.
Chief complaint:
Does patient complain of dry mouth?
Yes No
Dry mouth questionnaire:

1. Does the amount of saliva in your mouth seem to be too little?
2. Do you have any difficulties swallowing?
3. Does your mouth feel dry when eating a meal?
4. Do you sip liquids to aid in swallowing dry foods?
Yes No
Medical history and review of systems:

Does patient have any known risk factors?
Yes No
Clinical evaluations:
Does patient manifest any of the following conditions?
Major salivary glands: Lips: Mucosa/tongue: Dentition:

Enlarged? Dry? Dry? Extensive restorative
Tender? Chapped? Erythematous? experience?
No saliva upon palpation? Fissured? Lobulated? Rampant caries?
No saliva pool? Erythematous? Fissured? Caries involving
Saliva contaminated incisal, cervical,
with pus or blood? or root surfaces?
Yes Yes Yes Yes
Consider further diagnostic work up:

Sialometric evaluation
Serologic evaluation
Microbial analysis
Histologic evaluation
Imaging
Nutritional counseling
Medical consult
Psychological evaluation
Fig. 9.1 Identifying patients with or at risk for chronic salivary gland hypofunction
9 Salivary Gland Dysfunction and Xerostomia 93
• Identify patients at risk of development of xerostomia and/or salivary gland

dysfunction.
• Identify patients with existing xerostomia and/or salivary gland dysfunction.
• Assess the severity of existing or evolving complications associated with salivary
gland dysfunction.
• Identify and, if possible, eliminate the risk and/or etiologic factors.
• Make referrals to other healthcare providers if needed for the management of
systemic conditions.
• Utilize evidence-based decision making and evolving scientific information.
• Implement patient-centered individualized strategies to prevent onset or progres-
sion of complications associated with salivary gland dysfunction.
• Restore form and function of affected structures and manage other existing com-
plications caused by salivary gland dysfunction.
• Monitor management outcomes and reassess efficacy of implemented plan and
treatment. Revise plan accordingly if needed.
Treatment modalities vary based on the etiology and severity of existing conditions
and may include:
• Stimulation of saliva secretion: non-cariogenic sialagogues

• Hydration
• Lubrication
• Saliva replacement (saliva substitute)
• Dietary modifications
• Psychiatric and behavioral counseling for coping strategies and to reduce behav-
ioral and lifestyle factors associated with the condition
• Pharmacotherapeutic interventions
• Surgical approaches
Several potential treatment approaches have been explored and studied recently
(e.g., gene therapy, cell therapy), and these will be discussed in detail in the follow-
ing two chapters.
9.8 Treatment Goals and Sequence of Care
The above treatment options are aimed for increasing the oral cavity moisture by
lubricating the intraoral soft and hard tissues with stimulated saliva or by taking
saliva substitutes.
The first line of treatment should focus on improving oral hygiene consistently
with non-cariogenic sialagogues in the form of topical, gel, spray, or mouthrinses.
94 M. Navazesh
The use of cholinergic medications should be carefully evaluated if patient has a

complex medical history or is under a polypharmacy treatment regimen.
Suggested Readings
1. Jensen SB, Pedersen AML, Vissink A, et al. A systematic review of salivary gland hypofunc-
tion and xerostomia induced by cancer therapies: prevalence, severity and impact on quality of
life. Support Care Cancer. 2010;18(8):1039–60. doi:10.1007/s00520-010-0827-8.
2. Villa A, Wolff A, Aframian D, et al. World workshop on oral medicine VI: a systematic review
of medication-induced salivary gland dysfunction: prevalence, diagnosis, and treatment. Clin
Oral Invest. 2015;19:1563–80. doi:10.1007/s00784-015-1488-2.
3. Löfgren CD, Wickström C, Sonesson M, et al. A systematic review of methods to diagnose
oral dryness and salivary gland function. BMC Oral Health. 2012;12:29.
doi:10.1186/1472-6831-12-29.
4. Luciano N, Valentini V, Calabrò A, et al. One year in review 2015: Sjögren’s syndrome. Clin
Exp Rheumatol. 2015;33(2):259–71.
5. O’Connor R, David MA, Peter BA. Focused review of investigation, management and out-
comes of salivary gland disease in specialty-specific journals. Br J Oral Maxillofac Surg.
2014;52(6):483–90. doi:10.1016/j.bjoms.2014.03.016.
6. Turner L, Mupparapu M, Akintoye SO. Review of the complications associated with treatment
of oropharyngeal cancer: a guide to the dental practitioner. Quintessence Int. 1985;44(3):267–
79. doi:10.3290/j.qi.a29050.
7. Spolarich AE. Risk management strategies for reducing oral adverse drug events. J Evid Base
Dent Pract. 2014;14:87–94. doi:10.1016/j.jebdp.2014.04.009.
8. Davies A, Bagg J, Laverty D, et al. Salivary gland dysfunction (‘dry mouth’) in patients with
cancer: a consensus statement. Eur J Cancer Care. 2010;19(2):172–7. doi:10.1111/j.1365-2354.
2009.01081.x.
9. Jensen SB, Pedersen AML, Vissink A, et al. A systematic review of salivary gland hypofunc-
tion and xerostomia induced by cancer therapies: management strategies and economic impact.
Support Care Cancer. 2010;18(8):1061–79. doi:10.1007/s00520-010-0837-6.
10. Kałużny J, Wierzbicka M, Nogala H, et al. Radiotherapy induced xerostomia: mechanisms,
diagnostics, prevention and treatment–evidence based up to 2013. Otolaryngol Pol.
2014;68(1):1–14. doi:10.1016/j.otpol.2013.09.002.
11. Hanchanale S, Adkinson L, Daniel S, et al. Systematic literature review: xerostomia in
advanced cancer patients. Support Care Cancer. 2015;23(3):881–8. doi:10.1007/
s00520-014-2477-8.
For Further Information Visit the Following Websites

12. http://www.nidcr.nih.gov
13. http://www.sjogrens.org
14. http://www.nci.org
Gene Therapy for Radiation-Induced
Salivary Hypofunction 10
Bruce J. Baum
Pearls of Wisdom
• Often patients who have radiation-induced salivary hypofunction are told
by their surgeons or oncologists that they should be happy “they are cured”
and not complain about a “minor side effect,” i.e., a small problem such as
having too little saliva due to their cancer treatment. Even patients for
whom gene or pharmacological therapy are not options benefit greatly
from a clinician’s attention and careful instructions on how to care for their
oral health and how to chew and swallow deliberately.
• It must be recognized that gene therapy is still in its developmental stages.
The vectors used now to transfer genes into salivary glands and other tis-
sues doubtless will be viewed as primitive in one to two decades.
• Indeed, it may be feasible within a decade or so to prevent radiation dam-
age to healthy salivary glands using gene transfer technology alone or in
conjunction with improved advanced radiotherapy techniques and/or phar-
macological agents.
10.1 Introduction and Diagnostic Subtypes
This chapter primarily will focus on the use of gene therapy to correct radiation-
induced salivary hypofunction but of necessity addresses how a clinician would
determine that a patient with this condition is a candidate for gene therapy.
B.J. Baum, DMD, PhD

National Institutes of Health Scientist Emeritus, Molecular Physiology and Therapeutics
Branch, National Institute of Dental and Craniofacial Research, National Institutes of Health,
Department of Health and Human Services, Bethesda, MD, USA
e-mail: bbaum@dir.nidcr.nih.gov
© Springer International Publishing Switzerland (outside the USA) 2017 95

J.N.A.R. Ferreira et al. (eds.), Gene Therapy for Radiation-Induced Salivary
Hypofunction, DOI 10.1007/978-3-319-51508-3_10
96 B.J. Baum
Salivary hypofunction refers to a reduction in salivary flow [1, 2]. It is an objec-

tive term, i.e., determined by measuring salivary fluid output from individual
glands (gland saliva) or from the entire mouth (whole saliva, i.e., expectoration).
Salivary flow can be measured in the absence or presence of stimulation. Typical
stimuli used include swabbing the tongue with 2% citric acid, sucking a sugarless
lemon drop, or chewing dental wax. Xerostomia refers to a subjective complaint,
a symptom, reported by a patient that indicates the individual is having the
sensation of a dry mouth [1, 2]. It most frequently, but not always, is associated
with salivary hypofunction. Both salivary hypofunction and xerostomia are com-
monly seen in patients following radiation therapy for head and neck cancers, but
also frequently observed in patients with the autoimmune disorder Sjögren’s
syndrome, and in patients using certain commonly prescribed medications, e.g.,
opiates, anticholinergics, antidepressants, or common over-the-counter drugs,
e.g., antihistamines.
Whatever the etiology of the salivary hypofunction, patients typically present with
one or more of the following symptoms or signs:
• Dry mouth
• Difficulty swallowing (inability to form and translocate a food bolus in the mouth)
• Oral mucosal sores (due to the absence of growth factors and antimicrobial pro-
teins from saliva that help heal oral sores)
• Burning tongue (often associated with Candida infections because of the absence
of saliva’s antifungal proteins)
• Bad breath (inability to clear food and microbial debris due to too little salivary
fluid)
• Pain (often related to increased caries activity due to the loss of salivary antimi-
crobial proteins and remineralizing proteins)
True salivary hypofunction is accompanied by a reduction in saliva flow [1, 2].

If a clinician does not already have salivary flow information for their patient
prior to any complaints, then the saliva output determined following a patient’s
complaint must be compared with population values. However, for an individ-
ual patient, the use of population standards may not be helpful. For example,
normal values for both unstimulated and stimulated saliva output from glands
can easily vary by an order of magnitude [3]. Similarly, for whole saliva, there
is wide variance. Thus, the normal output for some people may be
1.25 mL/15 min, while for others it may be 3 mL/15 min (or much more). If the
latter individuals experience a reduction in whole saliva output from 3.0 to
1.5 mL/15 min, for whatever cause, they will likely experience a dry mouth,
even though their saliva output is greater than the former individuals, who are
comfortable and accommodated to producing lower levels of saliva in their
mouth.
10 Gene Therapy for Radiation-Induced Salivary Hypofunction 97
As noted earlier, this chapter is focused on the use of gene therapy to treat radiation-
induced salivary hypofunction, i.e., the etiology is clear. Each year in the United States,
there are 40,000–50,000 individuals diagnosed with head and neck cancers [4], while
worldwide there are ~500,000 persons affected by this condition. For almost all of
these patients, treatment typically includes radiotherapy, and salivary glands in the field
of radiation are significantly damaged. Most of these patients will experience salivary
hypofunction, and for a great many of them, the damage will be permanent [5].
Salivary glands are like a bunch of grapes. The latter have fruit (berries) and stems,
while the former have, analogously, the acinar cells and the duct cells. Acinar cells
are like the berries and are the sole site of exocrine fluid movement in these glands
[6], secreting a so-called primary fluid that is then modified by the ducts. When
acinar cells are damaged or lost, for whatever reason, it is impossible for salivary
glands to secrete fluid. Duct cells are like the stems. In addition to functioning to
modify the primary fluid (reabsorb or secrete ions, secrete some proteins), the ducts
convey the saliva to the mouth. The exact mechanism of acinar cell damage follow-
ing radiation is not entirely clear, but it apparently involves multiple sites of injury
[7]. Whatever the mechanism (s), the absence of saliva leads to all the negative signs
and symptoms mentioned above under clinical presentation.
• Positive history of radiation therapy to the head and neck region, most likely for
the treatment of a malignancy.
• Visually low levels of whole saliva, which has a sticky or viscous consistency.
• A test of salivary stimulation, e.g., with 2% citric acid, which fails to elicit a
significant visual increase in salivary flow or sublingual pooling (this suggests it
is likely that all or most acinar cells have been lost or damaged).
• Oral signs such as increased dental caries, candidal infections, and/or frequent oral sores.
• No noticeable improvement in the sensation of oral moisture following the above
salivary stimulation.
• Complaints of a having dry mouth and/or a reported difficulty in swallowing.
• Additional testing, such as various types of diagnostic imaging and clinical labo-
ratory analyses, is typically not necessary.
The key factor in managing a patient with radiation-induced salivary hypofunction is

appreciating the relative amount of surviving acinar cells present [6, 8]. The abovemen-
tioned test of stimulation is a simple yet helpful tool for this determination. If there is
98 B.J. Baum
good stimulation, and the patient notices an improvement in oral moisture, then in all
likelihood there are a significant number of acinar cells that have survived the radio-
therapy. Conversely, if there is no increase in saliva output following stimulation, it is
reasonable to assume that most or all acinar cells have been lost or damaged. In between
these two extremes lies a range of possibilities that can be evaluated empirically when
treatment options are considered (below).
There are three general treatment options based on the above-described test of sali-
vary stimulation:
1. When there is good stimulation, the patient is not a candidate for gene therapy,
even if they complain of a dry mouth and have signs of salivary hypofunction. It
is clearly preferable to treat such a patient pharmacologically using either of two
well-established secretagogues, pilocarpine (Salagen) or cevimeline (Evoxac),
assuming there are no medical contraindications to their use. If there are such
contraindications, or if preferable to the patient, the clinician can consider using
an intraoral electrostimulation device [9].
2. When there is absolutely no stimulation detected and no improvement in oral
moisture noted, the patient likely has had almost all of their acinar cells lost and
a gland substantially replaced with fibrotic tissue. Currently, little can be done
for such a patient, other than palliative care, e.g., use of an artificial saliva, and
counseling related to careful oral hygiene and attentive chewing and swallowing,
to prevent choking and aspirations.
3. Between these extremes lie patients with some modest response to stimulation,
but one that is insufficient to provide much symptomatic or practical relief.
These patients likely have some acinar, and many ductal cells present, i.e., a
reasonable amount of epithelial tissue able to be “reengineered” to secrete fluid
via a gene therapy approach [6, 10].
10.7.1 Gene Transfer Strategies
There are two general ways to transfer genes into cells or intact animals, including
humans, using (i) viral vectors or (ii) nonviral methods (Table 10.1).
All of the above-indicated examples have been utilized in the salivary glands of
preclinical animal models, while at the time of this writing (March 2016) only an
Table 10.1 Methods used to transfer genes
Method of
gene transfer Examples Advantage Disadvantage
Viral vector Adenoviral, adeno-associated Relatively high level Safety concern due to
viral of gene transfer immune reactivity
Nonviral Plasmids ± liposomes ± Generally Generally lower level
polyethylenimine ± nanoparticles ± considered to be of gene transfer
microbubbles and ultrasound quite safe
adenoviral vector has been used in human salivary glands (see below). For the clini-
cal trial that my colleagues and I conducted using gene therapy to “repair” radiation-
damaged parotid glands, we previously described in great detail the reasons for
choosing the viral vector strategy employed, including gene selection and delivery
method (see [6, 8]). Thus, only the key points are listed below:
• Gene (cDNA) used encodes human aquaporin-1 (hAQP1), a water channel.

• Method to transfer the hAQP1 cDNA into the surviving salivary epithelial cells
used an adenoviral vector (AdhAQP1) via intraductal cannulation.
• The approach was beneficial in preclinical studies in rats and miniature pigs.
• Importantly, it was beneficial in a first-in-human clinical trial when administered
to a single parotid gland through Stensen’s duct [10].
• In the trial, 11 subjects were treated with AdhAQP1 at four escalating doses
(4.8 × 107, 2.9 × 108, 1.3 × 109, 5.8 × 109 vector particles).
• Efficacy was dose dependent, and, at the first three doses, five of the nine sub-
jects treated showed positive objective responses, i.e., increased parotid saliva
secretion, and improved subjective responses, e.g., reduced mouth dryness (1, 2,
and 2 at each respective dose; see Fig. 10.1).
a Parotid salivary flow rate b Proportional increase in peak

from the targeted gland salivery flow
p=0.032
0.6
600
Parotid saliva flow (ml/min)
Parotid saliva flow
500
as % of baseline
0.4 400
300
p=0.039
0.2 200
100
0.0 0
Pre-treatment Peak flow post-treatment Peak flow post-treatment
Fig. 10.1 AdhAQP1 trial clinical response data. Clinical responses following AdhAQP1 vector deliv-
ery as measured by (a) absolute parotid salivary flow rate from the targeted gland and (b) the propor-
tional increase in peak parotid salivary flow are shown as the percent of baseline. Significance was
determined using the Wilcoxon matched pair rank test for the change in absolute values. The Wilcoxon
signed rank test was used to test if the peak proportional increase in parotid salivary flow was signifi-
cantly different from the baseline (100%). Individual changes in parotid salivary flow are shown in (c)
for absolute salivary flow rates and in (d) for proportional changes compared to baseline. Coding for
individual subjects is shown as indicated in the panel (c) insert. All subjects shown in black were con-
sidered nonresponders (<50% increase in salivary flow rate). All subjects shown in colors were consid-
ered responders (six; at least a 50% increase in parotid salivary flow following AdhAQP1). The days
indicated to the right of each peak data point in panel (c) correspond to the days on which that peak
parotid flow rate was observed. Visual analogue scale (VAS) results from all subjects, at baseline and
peak time of parotid salivary flow, are shown for both the amount of saliva perceived ((e); rate how
much saliva is in your mouth) and dryness of their mouth ((f); rate the dryness in your mouth). Note that
lower VAS results indicate an improvement in symptoms. The colors and symbols used to identify
individual subjects are identical to those shown in panel (c). Five of the six subjects considered respond-
ers by flow rate increases (mentioned above) showed improvement in their symptoms (This figure is
reprinted from, and the legend slightly modified from, Fig. 2, originally published in Baum et al. [10])
100 B.J. Baum
c Absoluate change in saliva flow d Proportional change in salvia flow

0.6 700
40
25 4.8×103 Days
15
50 14 600
0.5 2.9×104
73
99
Percent changes in parotid saliva flow

105 2.3×103
118 500
0.4 103 7
4
Parotid Flow (ml/min)
5.8×104
116
400
0.3 42
300
28
0.2
2 200
2
3
0.1 28
7 100
14
28
0.0 0
Baseline Peak Baseline Peak
e Amount saliva f Dry mouth

10 10
8 8
6 6
VAS
VAS
4 4
2 2
0 0
Baseline Peak Baseline Peak
Fig. 10.1 (continued)
• At the highest dose, both treated subjects exhibited significant immune reactivity
to the adenoviral vector and no positive objective or subjective response to gene
delivery.
• Of particular import, there were no significant side effects to adenoviral vector
delivery in all 11 trial subjects (see Table 10.2).
At present, there are no other genes being tested to correct existing radiation
damage in salivary glands. However, the hAQP1 gene also can be successfully
transferred via an adeno-associated viral vector [11] and a nonviral vector
(ultrasound-assisted gene transfer; UAGT [12]) to parotid glands of miniature pigs.
Of note, UAGT employs suspending the hAQP1 cDNA in microbubbles and deliv-
ery in a similar retroductal infusion manner as used in the AdhAQP1 study. After
gene administration, an ultrasound pulse leads to disruption of the microbubbles
and facilitates entry of the gene to all cells with which it has contact.
There are two distinct approaches that have been reported in preclinical animal
models using gene transfer to prevent radiation damage to salivary glands, both
shown to work in rodents after retroductal delivery to submandibular glands. As yet,
these have not been tested in humans. In the first strategy (viral-based) [13], they
used rats as a model and transferred the tousled kinase 1B (TK1B is involved in
chromatin rearrangement) gene with an adeno-associated viral vector. In the second
approach (nonviral-based) [14], researchers used mice as a model and transferred a
short interfering RNA (siRNA) that blocks radiation-induced apoptosis; they have
used nanoparticles for siRNA transfer.
Table 10.2 Summary of adverse events

Dose tier (n) Grade 1 (mild) Grade 2 (moderate) Grade 3 (severe)
1 (3) 18a 2 0
2 (3) 19b 3 0
3 (3) 19c 1 0
4 (2) 3 0 0
Total (%) 59 (90.8%) 6 (9.2%) 0 (0%)
Data shown are the number of adverse events (grades 1, 2 or 3) recorded in each dosing tier.
Dosing tiers are numbered 1–4 for convenience and correspond, respectively, to 4.8 × 107,
2.9 × 108, 1.3 × 109, and 5.8 × 109 vector particles. The percentages shown are of the total number
of adverse events seen, i.e., 65
a
Five were judged possibly related to treatment
b
Three were judged possibly related to treatment
c
Two were judged possibly, four probably, and one definitely related to treatment (all with a single
subject)
All other adverse events (50/65; 76.9%) were judged as unlikely related or unrelated to treatment.
This table is slightly modified from one originally published in Baum et al. [10]
102 B.J. Baum
The primary objective of treating any patient with radiation-induced salivary hypo-
function, regardless of the treatment approach, is to increase their salivary output
and decrease the typical symptoms and signs associated with this disorder. The first
of these can be assessed objectively by measuring saliva flow before and after treat-
ment [1, 2]. Symptoms related to oral dryness can be quantified using a validated
visual analogue scale [15]. Another important patient complaint, difficulty swallow-
ing, can be readily assessed by examining the oropharyngeal phase of swallowing
with dynamic ultrasound imaging [16].
Acknowledgment I am extremely grateful to the Intramural Research Program of the National

Institute of Dental and Craniofacial Research for supporting my research and enabling everything
that is mentioned in this chapter. I am also extremely grateful to my many wonderful colleagues at
NIH and elsewhere who worked so hard to make a 1991 vision into a clinical reality.
References
1. Fox PC, van der Ven PF, Sonies BC, et al. Xerostomia: evaluation of a symptom with increas-
ing significance. J Am Dent Assoc. 1985;110:519–25.
2. Ship JA, Fox PC, Baum BJ. How much saliva is enough? Normal function defined. J Am Dent
Assoc. 1991;122:63–9.
3. Heft MW, Bruce BJ. Unstimulated and stimulated parotid salivary flow rate in individuals of
different ages. J Dent Res. 63:1182–5.
4. Siegel R, Ma J, Zou Z, Jemal A. Cancer statistics, 2014. CA Cancer J Clin. 2014;64:9–29.
5. Cox JD, Stetz J, Pajak TF. Toxicity criteria of the Radiation Therapy Oncology Group (RTOG)
and the European Organization for Research and Treatment of Cancer (EORTC). Int J Radiat
Oncol Biol Phys. 1995;31(5):1341–6.
6. Baum BJ, Zheng C, Alevizos I, et al. Development of a gene transfer-based treatment for
radiation-induced salivary hypofunction. Oral Oncol. 2010;46:4–8.
7. Vissink A, Mitchell JB, Baum BJ, et al. Clinical management of salivary gland hypofunction
and xerostomia in head-and-neck cancer patients: successes and barriers. Int J Radiat Oncol
Biol Phys. 2010;78:983–91.
8. Samuni Y, Baum BJ. Gene delivery in salivary glands: from the bench to the clinic. Biochim
Biophys Acta. 1812;2011:1515–21.
9. Strietzel FP, Lafaurie GI, Mendoza GR, et al. Efficacy and safety of an intraoral electrostimu-
lation device for xerostomia relief: a multicenter randomized trial. Arthritis Rheum.
2011;63:180–90.
10. Baum BJ, Alevizos A, Zheng C, et al. Early responses to adenoviral-mediated transfer of the
aquaporin-1 cDNA for radiation-induced salivary hypofunction. Proc Natl Acad Sci U S A.
2012;109:19403–7.
11. Gao R, Yan X, Zheng C, et al. AAV2-mediated transfer of the human aquaporin-1 cDNA
restores fluid secretion from irradiated miniature pig parotid glands. Gene Ther.
2011;18:38–42.
12. Wang Z, Zourelias L, Wu C, et al. Ultrasound-assisted nonviral gene transfer of AQP1 to the
irradiated minipig parotid gland restores fluid secretion. Gene Ther. 2015;22:739–49.
13. Timiri Shanmugam PS, Dayton RD, Palaniyandi S, et al. Recombinant AAV9-TLK1B admin-
istration ameliorates fractionated radiation-induced xerostomia. Hum Gene Ther.
2013;24:604–12.
14. Arany S, Benoit DS, Dewhurst S, Ovitt CE. Nanoparticle-mediated gene silencing confers
radioprotection to salivary glands in vivo. Mol Ther. 2013;21:1182–94.
15. Pai S, Ghezzi ES, Ship JA. Development of a visual analogue scale questionnaire for subjec-
tive assessment of salivary dysfunction. Oral Surg Oral Med Oral Pathol Oral Radiol Endod.
2001;91:311–6.
16. Chi-Fishman G, Sonies BC. Effects of systematic bolus viscosity and volume changes on
hyoid movement kinematics. Dysphagia. 2001;17:278–87.
Salivary Hypofunction in Aging Adults
11
Catherine Hong and João N.A.R. Ferreira
Pearls of Wisdom
• Rapid progression to an edentulous status due to rampant tooth decay,
opportunistic infections, inability to retain removable prostheses, discom-
fort during eating and speaking, burning sensation of the mouth, and
diminished taste acuity are some of the reported signs and symptoms of
dry mouth in aging adults.
• A variety of symptomatic measures are available to alleviate dry mouth
symptoms in the elderly, but these largely fall under two categories:
(1) saliva substitutes and lubricants and (2) saliva stimulants for local or
systemic application.
11.1 Introduction
Saliva is essential for the function and preservation of oropharyngeal health.

Xerostomia and salivary gland hyposalivation are used interchangeably to describe
dry mouth; however, it is important to distinguish between terms as persons suffer-
ing from xerostomia may not necessarily have hyposalivation. Salivary gland dys-
function is a condition in which either the chemical properties of saliva is altered or
when the unstimulated or stimulated salivary flow is significantly reduced. Salivary
hypofunction is generally defined as an unstimulated flow rate of less than 0.1–
0.2 ml/min and a stimulated saliva flow rate of less than 0.7 ml/min. Xerostomia
refers to the subjective perception of dry mouth and is sometimes but not always
accompanied by salivary gland dysfunction [1–3].
C. Hong, DDS, MS, Dip. AAOM

Orthodontics and Paediatric Dentistry, Faculty of Dentistry, National University of Singapore,
Singapore, Singapore
J.N.A.R. Ferreira, DDS, MS, PhD, Dip. ABOP (*)
Oral and Maxillofacial Surgery, Faculty of Dentistry, National University of Singapore,
e-mail: denjnarf@nus.edu.sg

DOI 10.1007/978-3-319-51508-3_11
106 C. Hong and J.N.A.R. Ferreira
11.2 Epidemiology
Clinical experts and researchers have proposed that salivary gland dysfunction and
xerostomia be considered as separate entities as studies conducted on prevalence of
xerostomia and salivary gland dysfunction have demonstrated that both conditions
existed together only about 2–5% of the time [3, 4]. In this chapter, for the purpose
of ease, the term dry mouth will be used when referring to both salivary gland dys-
function and xerostomia.
In patients with Sjögren’s syndrome and those who are undergoing head and
neck radiotherapy, the prevalence of dry mouth is almost 100%. However, the prev-
alence data of xerostomia and salivary gland hypofunction in the general population
is more difficult to ascertain and ranges widely due to both the heterogeneity of
sampled populations and varying definitions of dry mouth in the literature [5–7].
In a systematic review by Orellana et al. [8], it was reported that the prevalence
of xerostomia is approximately 20% in the community, but appears to be higher in
the elderly and institutionalized individuals. Ship et al. [3] estimate the prevalence
of xerostomia in adults aged 65 years and over to be 30% and up to 50% in institu-
tional elders. Presently, there is no convincing evidence that age is a significant
cause of dry mouth, and polypharmacy is still believed to be the leading cause of dry
mouth in this population. There are over 400 medications that cause dry mouth as a
side effect and with the increase of prescription medications with age; the preva-
lence of medication-induced dry mouth is expectedly higher in older individuals.
There are many other causes of dry mouth (e.g., Sjögren’s syndrome, head and neck
radiation, dehydration), which will not be discussed in this chapter as these have
been reviewed in Chaps. 9 and 10.
Although non-life-threatening, dry mouth can adversely affect oral health status
and has been associated with a myriad of subjective and clinical problems. Rampant
dental decay, opportunistic infections, inability to retain removable prostheses, dis-
comfort during eating and speaking, burning sensation of the mouth, and dimin-
ished taste acuity are some of the reported signs and symptoms of dry mouth in
aging adults [9, 10]. These can consequently impact the quality of general and oral
health and well-being particularly in the elderly.
A systematic approach should be used to distinguish and diagnose patients with

xerostomia and those with salivary gland hypofunction [11]. To begin, in-depth
exploration of the chief complaint with questions pertaining to oral dryness during
eating (e.g., need to sip liquids to swallow dry foods, difficulty swallowing) and
self-perception of amount of saliva must be elicited. Other questions pertaining to
feeling of dryness on awakening and during the night, speech difficulties, taste dis-
turbances, burning sensation, and intolerance to acidic and spicy foods may also be
elicited. For a comprehensive assessment, the Xerostomia Inventory (XI) is a useful
11-item validated instrument for assessing changes in symptoms over time [12].
11 Salivary Hypofunction in Aging Adults 107
Next, a thorough medical history to identify and rule out conditions (e.g.,
Sjögren’s syndrome), medical drug therapies (e.g., polypharmacy), and treatment
(e.g., head and neck radiation therapy) should be obtained. This should be followed
by a physical examination of the extra- and intraoral structures to identify signs of
hyposalivation. Extraoral findings include dry and cracked lips and enlarged unilat-
eral or bilateral salivary glands due to salivary obstructions or infections. Glossy
and sticky oral mucosa, depapillated, fissured, and erythematous tongue and lack of
salivary pooling in the floor of the mouth are some of the common findings intra-
orally. Saliva expression from the parotid ducts in the buccal mucosa and the sub-
mandibular ducts situated in the floor of the mouth should be performed routinely.
Cloudy or purulent discharge from the ducts may indicate an infection in the sali-
vary glands.
Due to the loss of the various protective functions of saliva (e.g., lubrication,
immunologic, buffering capacity, oral clearance), individuals with salivary gland
hypofunction are at high risk for trauma, all forms of oral candidiasis (pseudomem-
branous, erythematous, median rhomboid glossitis, and angular cheilitis), and den-
tal caries.
The objective measure of salivary production is essential to differentiate between
xerostomia and salivary gland hyposalivation. There are several methods of measur-
ing unstimulated (UWS) and stimulated whole saliva (SWS); the most common
collection method for unstimulated salivary flow rate in clinical practice is the spit-
ting or drooling method [11]. This method is favored as it does not require special
equipment, is easily administered, and is reproducible [13]. The UWS rate is mea-
sured by the patient allowing saliva to accumulate in the mouth for 5 min and spit-
ting into a collection tube and then repeating this for a 15 min period. Alternatively,
the patient may incline his or her head forward and drool into a receptacle for the
same amount of time. For SWS rate, this can be measured by having the patient
chew on a piece of paraffin wax or using a sialagogue such as 4–10% citric acid.
There are other methods for measuring salivary flow such as the use of suction cups
over the parotid gland; however, these tend to be used for experimental studies to
obtain measurements of flow from selected major salivary gland. A UWS of less
than 0.1–0.2 ml/min and a SWS flow rate of less than 0.5–0.7 ml/min are considered
indicative of hyposalivation [11, 14].
Salivary gland abnormalities can also be identified by a variety of imaging tech-
niques. Plain radiography is an inexpensive and simple investigative tool to evaluate
the salivary gland; however, its use is limited due to its ability to only provide a
two-dimensional view of a three-dimensional structure. Scintigraphy involves the
injection of a radiopaque compound (99mtechnetium pertechnetate) into the blood.
Tc is then selectively taken up into the salivary glands which can then be visualized
and graded for disease process. Another technique that has been traditionally used
is sialography which involves a radiopaque compound medium being directly
introduced in the duct of the major salivary gland and the resulting image (sialo-
gram) used to visualize anatomy and integrity of ducts and acinar as well as obstruc-
tions from calcifications and tumors. However, conventional sialography has fallen
out of use due to the improved ability of modern imaging procedures such as
ultrasonography and MRI (magnetic resonance imaging) to assess salivary gland

abnormalities. These methods are noninvasive as they do not possess the risks asso-
ciated with conventional sialography (e.g., rupture of ductal system, allergy to con-
trast agent, radiation exposure). MRI sialography can define the ductal system of a
salivary gland without injection of a contrast agent and is able to demonstrate char-
acteristic changes in parotid glands (typically a nodular pattern, characterized by
multiple hypo- and hyperintense areas of varying size) associated with Sjögren’s
syndrome (SS). However, the imaging modality uses patient’s own saliva as a con-
trast agent as such resulting image resolution may be poor in patients with no or
minimal saliva production. Ultrasonography has been shown to demonstrate charac-
teristic salivary gland changes (e.g., multiple hypoechoic areas with convex borders,
hyperechoic linear bands, cysts and calcifications in advanced disease) in SS with
diagnostic value comparable to traditional methods such as scintigraphy and sali-
vary gland biopsy. Computed tomography can also be used to evaluate structural
abnormalities of salivary gland; however, its use is limited compared to ultrasonog-
raphy and MRI due to the involvement of ionizing radiation [15].
Salivary gland biopsy provides a definitive diagnosis of gland pathology. Biopsy
of labial minor salivary glands is commonly preferred over biopsy of a major gland
for the diagnosis of Sjögren’s syndrome as it is more accessible with fewer compli-
cations [16]. The presence of at least one focus area of periductal lymphocytic infil-
tration is consistent with the diagnosis of Sjögren’s syndrome. A focus is defined as
an agglomerate of at least 50 mononuclear cells in 4 mm2 of tissue.
Other investigations include blood tests to assess for hematinic deficiencies and sero-
logical tests to identify antibodies to diagnose diseases with salivary gland pathology.
11.4 Treatment Rationale and Goals
After the diagnosis of dry mouth has been made, a stepwise management approach
is often taken. The primary goals are alleviation of symptoms, avoidance strategies,
and prevention of complications (e.g., dental caries, oral candidiasis) arising from
dry mouth.
11.5 Sequencing of Care
11.5.1 Alleviation of Symptoms
There are a variety of symptomatic measures available to alleviate symptoms in

aging adults, and these largely fall under two categories: (1) saliva substitutes and
lubricants and (2) saliva stimulants for local or systemic application.
Salivary substitutes and lubricants (e.g., Biotene Oral Balance Moisturizing Gel®,
Caphosol®, GC Dry Mouth Gel®, Oramoist®, Oasis®) frequently contain a mix of car-
boxymethylcellulose, mucopolysaccharides, polythene gycol, natural mucins, sorbi-
tol, and electrolytes to provide more viscosity and lubrication than water. In general,
these products have been shown to improve the subjective complaint of xerostomia
but not salivary flow. Additionally, saliva substitutes and lubricants are rarely effec-
tive beyond a few hours, and patients need to use them repeatedly over the course of
the day for continued comfort. Frequent sips of water can relieve symptoms, but
water does not provide lubricating properties, and excessive sipping of water may
strip the mucosa of the mucus film and increase symptoms.
Local stimulation of saliva through sugar-free gums and mints has also been
demonstrated to increase saliva production in individuals with residual secretory
function [17]. However, there is no strong evidence to support a specific type of sali-
vary substitute or stimulant, as such patients should try several agents and use
agent/s (singly or in combination) that provide them the greatest relief [17].
In patients who do not achieve sufficient symptomatic relief with saliva substi-
tutes/lubricants and topical stimulants, systemic saliva stimulants can be prescribed.
Muscarinic agonists such as pilocarpine nonspecific muscarinic agonist) and cevime-
line (specific muscarinic agonist with higher affinity for receptors on the lacrimal and
salivary epithelium) have been demonstrated in several clinical trials to improve sali-
vary flow and complaints of xerostomia compared to placebo [18–20]. Both medica-
tions have not been compared directly to each other but appear equally efficacious.
Adverse effects are frequent in both medications, though cevimeline being a selec-
tive muscarinic agonist may have a more favorable adverse effects profile than that
of pilocarpine, which is desirable in elderly patients. The typical dose for pilocarpine
is 5–7.5 mg orally four times daily; for cevimeline, the usual dose is 30 mg orally,
three times a day. It is recommended that the medications be taken about a half-hour
before meals. When initiating therapy, it is advisable to slowly titrate the dose of
pilocarpine or cevimeline upward (e.g., one dose daily for the first week) to minimize
side effects such as sudden onset of sweating and nausea. In patients who are prone
to dyspepsia and gastric bloating, taking the medication with food or using a proton
pump inhibitor may minimize symptoms. In patients who are unable to tolerate the
side effects of the full dose, a reduced pilocarpine dose of 2.5 mg three times a day
or 5 mg once a day may still provide some benefit. Alternatively, the capsule or tablet
can be dissolved in water and be used as a rinse and spit regimen to minimize sys-
temic absorption. As the response is frequently delayed, patients should be placed on
the drug for at least 3 months’ duration to assess for therapeutic benefit and side
effects. Due to the cholinergic side effects, pilocarpine and cevimeline may be con-
traindicated in patients with pulmonary and cardiovascular conditions, gastric ulcers,
glaucoma, and urethral reflex and in patients on ß-blockers [18–20].
11.5.2 Avoidance Strategies
Elderly patients should be advised to avoid caffeine-containing, acidic, and alco-

holic beverages as these may be dehydrating locally or systematically and could
worsen oral dryness symptoms. Other measures that can alleviate symptoms of
xerostomia, dry eyes, and dry nasal mucosa include avoidance of medications that
may worsen oral dryness and use of humidifiers by the bedside during the night.
In oncological treatment for head and neck cancer, modern advances in radio-
therapy (e.g., intensity-modulated radiotherapy and image-guided radiotherapy)
have allowed for restriction of high-dose radiation region to the target volume thus
minimizing radiation dose to neighboring tissues. In the PARSPORT trial, whereby
94 patients with head and neck cancer were randomly assigned to intensity-modu-
lated radiation therapy or conventional radiotherapy, with a dose of 60–65 Gy,
severe xerostomia was significantly less common with those patients in the IMRT at
both 12 and 24 months [21].
11.5.3 Prevention of Complications
Dry mouth predisposes patients to dental caries and opportunistic infections (e.g.,
candidiasis) due to the loss of the protective functions of saliva. Thus, it is impera-
tive that patients maintain meticulous home care (tooth brushing, flossing) and a
non-cariogenic diet (e.g., avoid cariogenic sweet and sticky foods and frequent
snacking). Patients should visit their dentist every 3–6 months for oral cleanings and
hygiene; the frequency is dependent on the extent of dryness. Dentists should con-
sider frequent professional fluoride applications and formulate a customized pre-
ventive plan for their patients which may include the following:
(i) Fluoride supplementation with prescription strength (0.5% fluoride or 1.1%

sodium fluoride) fluoride toothpaste (Prevident®) or fluoride gels in custom
fitted trays daily
(ii) Topical antimicrobial agents such as chlorhexidine [22]
(iii) Adjunct agents such as supersaturated calcium phosphate rinses or bland
mouth rinses containing baking soda, bicarbonate, or xylitol [23]
11.5.4 Submandibular Gland Transfer
A small multicenter trial found that surgical transfer of the submandibular gland
from an uninvolved side of the neck to the submental space in head and neck cancer
patients prior to radiation is superior to the use of pilocarpine. However, this tech-
nique has not gained popularity due to the need for an elective invasive procedure
and has not been evaluated against newer radiation techniques (e.g., IMRT—
intensity-modulated radiation therapy) [24].
11.5.5 Investigational and Other Agents
Amifostine has been shown to reduce dry mouth in patients undergoing head and
neck radiation by acting as a scavenger of free radicals generated in tissues exposed
to radiation [25]. However, the value of amifostine is still unclear due to the paucity
of studies, mixed results, high cost, and side effects (potential increase in tumor
survival).
In summary, the management of salivary hypofunction and xerostomia in the
elderly is currently based on pharmacological approaches to alleviate the oral dry-
ness symptoms. These approaches largely fall under two main categories: (1) saliva
substitutes and lubricants and (2) saliva stimulants for local or systemic application.
Intraoral electrical stimulation in the mouth (e.g., tongue and palate, oral mucosa),
acupuncture, use of hydroxychloroquine (antimalarial drug), nizatidine (histamine
receptor antagonist) in Sjögren’s syndrome patients, and hyperbaric oxygen therapy
have shown some benefit on dry mouth, but there are very few studies with mixed
results and a high risk of bias when these approaches are used [26–28]. As such,
results need to be confirmed in larger-scale randomized clinical trials. The following
novel strategies are also being studied in animal models and in preclinical trials:
• Gene therapy to increase endogenous levels of water channels via ductal cannu-
lation of viral and nonviral vectors (siRNA). These have been discussed in detail
in Chap. 10.
• Use of other cytoprotective agents (e.g., tempol) [29].
• Autologous stem/progenitor cell transplantation and other stem cell therapies
[30, 31].
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of intravenous amifostine on xerostomia, tumor control, and survival after radiotherapy for
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J Radiat Oncol Biol Phys. 2005;63(4):985.
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Epub 2016 Dec 20.
Part V
Oral Parafunctions and Sleep Disorders
Oral Parafunctional Behaviors
12
Alan G. Glaros and James Fricton
Pearls of Wisdom
• Many oral parafunctional habits and their consequences will improve or
get worse with the passage of time as life circumstances change.
• To address patient requests for relief from suffering, the conservative,
reversible approaches recommended by the National Institute of Dental and
Craniofacial Research will speed relief without subjecting patients to com-
plex or irreversible dental treatments that have little evidence of efficacy.
• Splints are “cueing” devices that improve patients’ awareness of parafunc-
tions and help decrease their occurrence.
• Simple self-care strategies are easy to describe to patients but may be dif-
ficult for them to understand and implement. Providers will have greater
success recommending these techniques when their approach uses a com-
mitted, personalized approach to their patients and a willingness to engage
patients in finding workable strategies for implementing change.
• Online patient cognitive-behavioral training programs are available to sup-
port clinicians in finding the time and skills to teach patients to reduce
these risk factors and encourage normal healing and function.
12.1 Introduction
Oral parafunctional behaviors are a broad class of behaviors that can occur during
the day and at night. They are characterized by activation of the masticatory mus-
cles for purposes other than chewing, swallowing, and speaking. They can be distin-
guished from the functional behaviors of the masticatory muscles by their often
A.G. Glaros, PhD (*)

University of Missouri-Kansas City, Kansas City, MO, USA
e-mail: GlarosA@umkc.edu
J. Fricton, DDS, MS, Dip. ABOP
University of Minnesota, Minneapolis, MN, USA

DOI 10.1007/978-3-319-51508-3_12
116 A.G. Glaros and J. Fricton
repetitive, non-goal-oriented actions. Behaviors such as clenching, grinding, and

tapping of teeth are clearly oral parafunctional behaviors.
Other common behaviors involving the masticatory muscles may also qualify as
oral parafunctional behaviors. These could include:
• Chewing gum
• Biting/chewing oral tissues (e.g., buccal mucosa, lips)
• Biting/chewing on nonfood objects (e.g., pens, pencils, erasers, fingernails)
Dr. Richard Ohrbach’s Oral Behavior Checklist can be used to assess a broad
range of oral parafunctional behaviors: http://www.rdc-tmdinternational.org/
Portals/18/Translations_other/Oral%20Behaviors%20Checklist%20v1-1%20-%20
English.pdf.
In addition, repetitive behaviors that are goal oriented but continuous can also
strain the teeth, jaw, and neck musculature. These behaviors may include playing
musical instruments with the mouth, scuba diving, and cradling a phone between
the head and the shoulders.
There is no formal nosology for diagnosing oral parafunctional behaviors that
accounts for the broad spectrum of behaviors involved. Some authors distinguish
between oral parafunctional behaviors that occur at night (“sleep bruxism”) and
those that occur during the day (“awake bruxism”) [1]. This distinction ignores
some commonalities in behavior between the two times. Grinding, extended tooth
contact (“clenching”), and tapping of the teeth can occur during sleep, whereas
awake bruxism is most likely to consist of extended tooth contact and other behav-
iors noted above.
Self-report and clinical signs are the two main methods by which patients present
with oral parafunctional behaviors. Both can provide useful information, but both
must be approached cautiously in a clinical setting.
A patient self-report of oral parafunctional behaviors may be limited to a small
number of such behaviors. To get a more complete sense of the breadth of these
behaviors, clinicians should ask patients about each type of oral habit and the fre-
quency of oral habits (Table 12.1).
Most patients can readily detect whether or not their teeth are touching at any
given time [2]. However, self-report of “clenching” or “bruxism” can produce unre-
liable results, as the terms have different meanings for different individuals. For this
reason, clinicians should use terms that have clear behavioral referents such as
“holding your teeth together,” not summary terms such as “clenching.”
Family members, friends, and colleagues may be reliable sources of information
about some oral parafunctional behaviors. For example, individuals who engage in
sleep-related grinding also create noise when they sleep. Bed partners or others who
12 Oral Parafunctional Behaviors 117
Table 12.1 Screening Have you or others noticed yourself doing any oral habits
questionnaire for self-report regularly (more than once a week)?
of oral habits Yes No
Chewing on one side □ □
Leaning on the jaw □ □
Grinding the teeth at night □ □
Grinding your teeth when awake □ □
Waking up with sore jaws □ □
Clenching your teeth when awake □ □
Clenching your teeth at night □ □
Holding your jaw forward □ □
Chewing gum □ □
Playing a musical instrument with the mouth □ □
Sleeping on stomach □ □
Touching or holding your teeth together □ □
Holding or pressing the tongue against your teeth □ □
Holding your jaw in a rigid or tense position □ □
Biting objects (pens, toothpicks, etc.) □ □
Biting your cheeks □ □
Biting your nails or cuticles □ □
Biting your lips □ □
Biting tongue □ □
Bracing the phone with the shoulder or jaw □ □
Table 12.2 Objective Yes No

indicators of oral habits
Tooth wear on front teeth □ □
Tooth wear on posterior teeth □ □
Mucosal ridging □ □
Tongue ridging □ □
Masseter hypertrophy □ □
Cheek biting □ □
Lip biting □ □
sleep nearby may provide useful information on sleep-related grinding, but patients
themselves are highly unreliable sources of information about their own sleep-
related grinding [3].
The signs of oral habits include tooth wear and fracture, masticatory muscle and
TMJ tenderness, tongue or cheek ridging, and other extra- and intraoral changes
(Table 12.2). When sleep-related oral parafunctions involve grinding, the teeth will
show atypical wear facets, fracture, or crazing of the enamel (Fig. 12.1). However,
because the presence of abnormal wear patterns is a historical record, the presence
of such patterns cannot be used as a reliable indicator of current, ongoing clenching
and grinding.
Fig. 12.1 Abnormal tooth wear caused by tooth grinding
Masticatory muscle and TMJ tenderness are more strongly related to extended
tooth contact, gum chewing, fingernail biting, and other day activities [4] than noctur-
nal habits. Morning muscle soreness is not a reliable sign of sleep-related grinding.
In some individuals, oral parafunctional habits manifest themselves extraorally
as hypertrophy of the masticatory muscles, especially the masseters or temporalis.
In some individuals, direct visualization of the buccal mucosa or inner lips will
indicate whether patients chew on their tissues. Evidence of such parafunctions will
often present as a thin line of lacerated tissue or a patch of shredded tissue about
where the teeth meet. Bracing of the tongue against the teeth will contribute to a
scalloping ridge on the lateral border of the tongue. Likewise, oral suction will com-
press the buccal mucosa against the teeth and contribute to scalloping ridge at the
teeth line on the buccal mucosa.
12.3 Epidemiology
Worldwide studies show that about 8% of the adult population engage in sleep-
related tooth grinding. Nocturnal grinding can occur as teeth erupt in children and
is often, though intermittently, reported in children. The proportion of children who
continue teeth grinding into adulthood is small.
Tooth contact is orders of magnitude more frequent than the 17.5 min commonly
reported in some dental textbooks [5]. Studies suggest that tooth contact occurs in
normal control subjects between 25% and 45% of the day (i.e., 4 h to more than 7 h
while awake), while those reporting temporomandibular disorder pain report tooth
contact nearly 75% of the day (i.e., as much as 12 h while awake). Other forms of
oral parafunctional behaviors appear to be relatively frequent, although most of the
studies use retrospective questionnaire data to estimate frequencies of these behav-
iors. Little is known about prevalence rates of these behaviors across the life-span.
Nocturnal tooth grinding is a sleep-related disorder [6]. Patients who grind differ from
those who do not on a variety of sleep variables, particularly those involving micro-
arousals. Some medications, including stimulants used for ADHD or selective sero-
tonin re-uptake inhibitors (SSRIs) for depression, may produce sleep-related grinding.
In some individuals, tooth grinding may protect against acid reflux during sleep.
The etiology of other diurnal oral parafunctional behaviors is less clear. Some
findings have associated daytime oral parafunctional behaviors with stress and anxi-
ety, the development of adjunctive behaviors, and deficits in proprioceptive aware-
ness. Some parafunctions may simply represent behaviors that that were learned in
childhood and have persisted into adulthood. Some individuals with variations in
gene coding for COMT are at higher risk for facial pain.
Older theories focusing on abnormal occlusion have not been substantiated as
valid causal factors in most oral parafunctional behaviors. Most individuals who
engage in oral parafunctional behaviors are no different occlusally than those who do
not engage in parafunctions. Studies reporting occlusal differences between indi-
viduals who engage in oral parafunctional behaviors and those who do not typically
fail to replicate.
There are no criteria for establishing a diagnosis of oral parafunctional behaviors.

Indeed, some authors argue that even sleep bruxism, the most well-studied of the
oral parafunctions, does not meet recognized criteria for being a diagnosable condi-
tion. If oral parafunctions are viewed as behaviors that can be measured, both clini-
cians and researchers can access questionnaires and devices that can provide useful
information about the parafunctions:
1. A simple questionnaire can act as screening tool for identifying different types
of behavioral patterns (Table 12.1).
2. Sleep polysomnography is the “gold standard” for identifying sleep-related oral
parafunctional activity. During sleep polysomnography, electroencephalographic
activity, electromyographic activity, electrooculographic activity (to record eye
movement), respiration, pulse oximetry, electrocardiogram, blood pressure, and
body temperature are typically collected, along with video or audio recordings.
Polysomnographic criteria for sleep-related grinding have good sensitivity and
specificity for identifying sleep-related grinding when examining those with a
very clear, current history of the behavior vs. those without any evidence of
grinding. Sleep polysomnography is expensive and time-consuming.
3. The “Bruxcore” monitoring plate is an alternative to the cost and intrusive char-
acteristics of sleep polysomnography. The Bruxcore monitoring plate is an intra-
oral appliance fabricated from four layers of plastic laminated to a total thickness
of 0.02 in., with microdots printed on the top surface. Grinding on the Bruxcore
plate wears away the microdots and exposes the colored layers (Fig. 12.2). A
quantitative score can be developed to express the degree of grinding [7].
4. Portable EMG devices specifically designed to capture tooth grinding show
some promise, although the quality of information from these devices is not
equivalent to information obtained from sleep polysomnography. For example,
these devices can presently detect intensive tooth contact but may not be able to
distinguish between oral parafunctional behaviors and sleep-related artifacts
such as turning in bed [8]. Advances in miniaturization make it increasingly
likely that devices will be manufactured that reliably accomplish all these tasks.
5. Experience sampling methods (ESM), also known as ecological momentary assess-
ment, can be used to diagnose the frequency and intensity of oral parafunctional
behaviors (Fig. 12.3). ESM is characterized by repeated measurement of a behavior
in a person’s natural environment. Data collection occurs several times per day, pref-
erably on a random schedule to avoid behavior changes due to the anticipation of a
Fig. 12.2 Evidence of

grinding as measured by
the Bruxcore device
(Reprinted from Isacsson
et al. [3])
data collection. ESM can assess the frequency and intensity of tooth contact, gum
chewing, cheek biting, and other activities that occur during the day.
The mechanism used to trigger recording can vary from the very low-tech (e.g.,
brightly colored stickers) to sophisticated electronic strategies. An example of the
latter is the Participation in Everyday Life (PIEL) Survey tool (https://pielsurvey.
org). This free application, available only for Apple products at the present time,
takes advantage of smartphone/tablet interfaces and can be readily programmed to
Fig. 12.3 Screenshots of sample ESM questionnaire items using PIEL survey tool
present push buttons, check boxes, sliders, etc. for assessment purposes. The amount
of time needed to train patients to use a smartphone-based ESM assessment strategy
is typically quite short, as patients are already used to interacting with their devices.
Treatment for teeth grinding is designed primarily to prevent further damage to the
teeth. There is no evidence that teeth grinding behaviors can be permanently altered
by dental, behavioral, or pharmacological interventions.
Treatment for other oral parafunctional behaviors such as extended tooth contact
(“clenching”) and cheek biting has reduction of injury to the masticatory system
and other oral tissues and their subsequent signs and symptoms as the primary
goals. This may include reducing pain, jaw dysfunction, soft tissue lesions, tooth
fractures, and other consequences.
Splints For sleep-related grinding, the use of an intraoral stabilization-type (“flat

plane”) appliance is suggested. These devices cover all the occlusal surfaces of a
dental arch and are typically fabricated from acrylic. This design allows grinding
motions to occur and does not “lock” the jaw into a fixed position. Grinding patients
only need to wear the device during when the likelihood of grinding is high (i.e.,
typically during sleep, but not during awake times). The appliance does not perma-
nently reduce grinding, and patients may need to use the device for many years.
For oral parafunction-related pain, a wide range of intraoral appliances have
been devised, including anterior/canine guidance, flat plane, anterior repositioning,
posterior group function, pivot, neuromuscular, and soft splints have been used.
There is no consensus on the amount of time that patients should wear these devices
or what the mechanism of action that accounts for their apparent utility in treating
pain. Depending on the behaviors involved, splints may be used during the day
and/or at night. As pain diminishes, patients can gradually reduce the amount of
time that they wear the devices.
Partial coverage splints such as those covering only the anterior or posterior teeth
or are worn full time must be carefully monitored to avoid super-eruption in the
non-covered teeth and resultant malocclusion. Appliances that are too thick may
cause remodeling of the TMJ and should therefore be used with caution.
Self-Care In all cases, splint use for oral parafunction-related pain should be
accompanied by provider counseling in self-care. Self-care methods can be quite
helpful to reduce habits. These include asking the patient to follow one or more of
these self-care strategies:
• Keep the tongue up, teeth apart, and jaw relaxed. Ask patients to closely monitor
the jaw position during their waking hours to maintain a relaxed comfortable jaw
position. This involves placing the tongue lightly on the palate (roof of the
mouth) where it is most comfortable and relaxing the jaw muscles. This tongue
position can be achieved by softly saying “n” with the tongue on the roof of the
mouth. The upper and lower teeth should never be touching/resting together
except occasionally when they touch lightly with swallowing. Similarly, patients
should not be encouraged to clench against splints but to use the splint as a
reminder to initiate self-care strategies.
• Avoid oral habits and oral parafunctional behaviors. Reducing or avoiding habits
such as gum chewing and biting on pencils or pens can help reduce the conse-
quences of these behaviors. The responses patients provide to the oral habits
checklist (Table 12.1) will offer multiple possibilities for intervention on oral
habits.
• Practice relaxation with diaphragmatic (abdominal) breathing. One simple way
to teach this skill is to ask patients to recline and place one hand on the chest and
one on the stomach. Instruct patients to breathe so that the stomach hand moves
up and down with each inspiration and exhalation, respectively, while chest hand
does not move. Daily practice of this relaxation technique will reduce patients’
reactions to stressful (and not so stressful) life events and help patients reduce
muscle tension, including tension in the masticatory muscles.
• Avoid caffeine. Caffeine is a “muscle-tensing” drug and can make muscles
tighter and contribute to rebound headaches. Caffeine and caffeine-like drugs
can be found in in coffee, tea, soda, chocolate, and some aspirin compounds.
Nocturnal alarms have been used to treat sleep-related masticatory muscle activ-
ity (Fig. 12.4). Typically, these devices monitor masticatory EMG activity or sounds.
When the activity exceeds a threshold for a given period of time, an alarm sounds
and wakes the patient to terminate the grinding/clenching behaviors. Some devices
use a mild electrical stimulus in place of an alarm. Other strategies, including release
of a liquid with an aversive taste, have also been used.
Nocturnal alarms can temporarily reduce bruxing behaviors. However, the
alarms disrupt sleep. Patients who use nocturnal alarms may report sleepiness and
difficulty concentrating while the alarm is being used. Discontinuation of the alarm
may lead to “rebound” in the level of grinding.
Fig. 12.4 Nocturnal alarm

Medication Pharmacologic approaches are used to manage both oral parafunctions

and parafunctional-related pain [9]. These include muscle relaxants for muscle-
tensing habits, Botox injections, and nonsteroidal anti-inflammatories (NSAIDs),
over-the-counter analgesics, and low doses of tricyclic antidepressants for pain.
Muscle relaxants and anxiolytics are used to manage anxiety, muscle tension,
and to improve sleep. Common side effects of sedation are rash and dependency on
benzodiazepines. Examples include:
• Cyclobenzaprine 10 mg HS
• Clonazepam 0.5 mg HS
Botulinum toxin (“Botox”) injections have been successfully used to treat

patients presenting with “bruxism” and orofacial pain. However, the long-term effi-
cacy, side effects, and impact on the functioning of the masticatory system of this
treatment are unknown.
NSAIDs often begin with high doses of the drug (400–800 mg dose QID, or two
to four times the maximum amount recommended for their over-the-counter equiva-
lents), with monitoring for gastrointestinal side effects such as pain or bleeding.
Providers must pay careful attention to other medications that patients are taking
and make sure that drug combinations do not inadvertently result in untoward side
effects. COX-2 inhibitors are often better tolerated by patients and have fewer gas-
trointestinal effects. The relationship of COX-2 use with cardiovascular events is an
area of concern.
Examples of NSAIDs that can help with jaw pain include:
• Naproxen 250 mg TID with meals

• Ibuprofen 400 mg TID with meals
• Celecoxib (Celebrex) 25 mg BID
Low doses of tricyclic antidepressants (TCAs) can successfully be used for oral
parafunction-related pain. Extrapyramidal effects, especially sleepiness and dry mouth,
can be mitigated by taking the medications before sleep or through the use of TCAs
with a lower incidence of extrapyramidal effects (e.g., nortriptyline). Extrapyramidal
effects often diminish with longer-term use. Among the conditions that providers
should attend to when using TCAs are cardiovascular diseases. Examples include:
• Amitriptyline 25–50 mg HS
• Nortriptyline 25–50 mg HS
Cognitive-Behavioral Therapy Behavioral interventions can successfully treat oral

parafunction-related pain (Table 12.3). The goals of these interventions are to reduce
parafunctional activity directly, reduce activity of the masticatory muscles, identify
and manage triggers for increased habits and pain, and develop alternative methods
for managing the experience of pain. These interventions include relaxation training,
biofeedback, cognitive-behavioral pain management, and habit reversal. Online cog-
nitive-behavioral training programs can be found at www.preventingchronicpain.org
and other sites.
Table 12.3 Three steps involved in cognitive-behavioral treatment of oral habits [10]
1. Understanding why to change the old habit. Oral parafunctional habits place repetitive strain
on the muscles and joints that over time that can lead to tension, tenderness, and pain
2. Knowledge of new habit. The new habit to learn involves relaxing the jaw muscles, joints,
and tongue by keeping the tongue up, teeth apart, and jaw dropped and relaxed. Correct the
head and neck posture as well and take a deep breath or two to help with general relaxation
3. Practice. Take pauses throughout the day to check if the upper and lower teeth are together.
If they are, correct it with the new habit of tong ue up and teeth apart. Practice the new habit
two to three times per hour for 2 weeks. Routine awareness of incorrect oral habits will
increase the automatic replacement with the new habits. Permanent correction with new habit
will generally occur within 2 to 4 weeks
Following the recommendations of the National Institute of Dental and Craniofacial

Research (NIDCR), conservative treatments are recommended first. These include
self-care strategies, intraoral appliances, medications, and behavioral interventions.
Direct demonstration of the impact of tooth contact on the activity of the mastica-
tory muscles helps patients understand the need to minimize parafunctional
activity.
If first stage approaches are not adequate, cognitive therapies focusing on pain
management and more intensive behavioral and psychophysiological interventions
may be needed. If these are not successful, more extensive cognitive therapy, the use
of alarm systems, and a reevaluation of the presenting complaint may be needed.
References
1. Lobbezoo F, Naeije M. Bruxism is mainly regulated centrally, not peripherally. J Oral Rehabil.
2001;28:1085–91.
2. Glaros AG. Temporomandibular disorders and facial pain: a psychophysiological perspective.
Appl Psychophysiol Biofeedback. 2008;33:161–71.
3. Isacsson G, Bodin L, Seldén A, Barregård L. Variability in the quantification of abrasion on the
Bruxcore device. J Orofac Pain. 1996;10:362–8.
4. Glaros AG, Marszalek JM, Williams KB. Longitudinal multilevel modeling of facial pain,
muscle tension, and stress. J Dent Res. 2016;95:416–422.
5. Glaros AG, Williams K, Lausten L. The role of parafunctions, emotions and stress in predict-
ing facial pain. J Am Dent Assoc. 2005;136:451–8.
6. Manfredini D, Ahlberg J, Castroflorio T, Poggio CE, Guarda-Nardini L, Lobbezoo F. Diagnostic
accuracy of portable instrumental devices to measure sleep bruxism: a systematic literature
review of polysomnographic studies. J Oral Rehabil. 2014;41:836–42.
7. Lobbezoo F, Ahlberg J, Glaros AG, Kato T, Koyano K, Lavigne GJ, de Leeuw R, Manfredini
D, Svensson P, Winocur E. Bruxism defined and graded: an international consensus. J Oral
Rehabil. 2013;40:2–4.
8. Raphael KG, Janal MN, Sirois DA, Dubrovsky B, Klausner JJ, Krieger AC, Lavigne
GJ. Validity of self-reported sleep bruxism among myofascial temporomandibular disorder
patients and controls. J Oral Rehabil. 2015;42:751–8.
9. Hersh EV, Balasubramaniam R, Pinto A. Pharmacologic management of temporomandibular
disorders. Oral Maxillofac Surg Clin North Am. 2008;20(2):197–210.
10. Litt MD, Shafer DM, Kreutzer DL. Brief cognitive-behavioral treatment for TMD pain: long-
term outcomes and moderators of treatment. Pain. 2010;151(1):110–6.
Obstructive Sleep Apnea and Snoring
13
Antonio G. Romero and João N.A.R. Ferreira
Pearls of Wisdom
• Moderate-to-severe sleep-disordered breathing (SDB) is common in the
general population, particularly between ages 50 and 70.
• Obstructive sleep apnea (OSA) is a major public health concern presenting
a high associated risk for hypertension, cardiovascular disease, type II dia-
betes, and motor vehicle accidents. The dentist should always evaluate for
the presence of risk factors in patients with any signs of SDB.
• PSG is the gold standard for the diagnosis of OSA and sleep disorders.
• The CPAP device is still considered the most effective therapeutic approach for
the management of SDB in both adults and children; however, their side effects
and low adherence make clinicians look for alternative treatment options.
• Oral appliances (OA), especially mandibular advancement devices (MAD),
have become viable option for patients with mild-to-moderate OSA or
with primary snoring.
• The sleep physician should be the one providing an accurate diagnosis and
prescribe OA when indicated. The dentist is considered a key part of the
multidisciplinary management team for OSA.
• When using OA, then dentist should use custom-made ones allowing for
the titration of the device and should monitor closely the resolution of
OSA symptoms and possible side effects.
A.G. Romero, DDS, PhD, Dipl. ABOP (*)

Member American Academy of Dental Sleep Medicine and Fellow American
Academy of Orofacial Pain, Valencia, Spain
Invited professor University of Valencia, Valencia, Spain
Invited Professor Mini-residency of Dental Sleep Medicine, Tufts University, Boston, USA
e-mail: Antonio.Romero@uv.es
J.N.A.R. Ferreira, DDS, MS, PhD, Dipl. ABOP
Faculty of Dentistry, National University of Singapore, National University Hospital,
University Dental Cluster, Singapore, Singapore

DOI 10.1007/978-3-319-51508-3_13
128 A.G. Romero and J.N.A.R. Ferreira
Sleep-related breathing disorders in adults are a heterogeneous group of disorders

characterized by different abnormalities of respiration during sleep. The term sleep-
disordered breathing (SDB) has been used interchangeably with the term obstruc-
tive sleep apnea (OSA), which has been now supplanted by the term obstructive
sleep apnea–hypopnea (OSAH) syndrome. However, in strict terms, we should use
the term SDB to encompass the entire group of respiratory abnormalities occurring
during sleep, not only just the obstructive sleep events. Taking these terms in
consideration, the ICSD-3 classifies the sleep-relating breathing disorders as in
Table 13.1 below.
Although classically the spectrum of sleep-disordered breathing ranged from pri-
mary snoring to severe sleep apnea (Fig. 13.1) and that can be even considered the
better approach for the dentist to understand these types of disorders, it is important
to point out this aspect in order to keep a balance between the clinical presentation
and the rigor of the nomenclature in the sleep medicine field. The term obstructive
sleep apnea–hypopnea (OSAH) syndrome should only be applied when making
reference to the spectrum of disorders in the family of obstructive respiratory events,
including OSA among others.
Firstly, it is important to differentiate the terms OSA and central sleep apnea
(CSA) since it will have a definite impact in the treatment that we can provide to
our patients. Further, it will also define the role of the dentist or the orofacial pain/
oral medicine practitioner on the management of these conditions. Nevertheless,
OSA is the most common and serious medical condition and is characterized by
recurrent cessation or substantial reduction in breathing during sleep. OSA is
Table 13.1 Sleep-disordered 1. Obstructive sleep apnea disorders (OSA)

breathing disorders’ classification 2. Central sleep apnea disorders
3. Sleep-related hypoventilation disorders
4. Sleep-related hypoxemia disorders
5. Isolated symptoms and normal variants
Severe
OSA
Moderate
Mild
OSA
OSA
UARS
Fig. 13.1 Disease severity Primary snoring

spectrum of sleep-
disordered breathing
13 Obstructive Sleep Apnea and Snoring 129
Table 13.2 Types of sleep apnea conditions

Type of sleep
apnea Definition Comment
Obstructive Normal ventilation is reduced or It requires to measure the presence of
sleep apnea obstructed due to a partial or totalrespiratory effort (esophageal manometry
occlusion of the upper airway or induction plethysmography required)
Respiratory effort is maintained Thoracic and abdominal belt sensors
required in home sleep testing devices
Central sleep Normal ventilation is reduced, but It is a central nervous system
apnea because the brain temporarily stops phenomenon. Thus it is not related to the
to send signals to muscles presence of the same predisposing factors
controlling breathing activity, the (leading to anatomic obstruction of the
effort to breathe is reduced or upper airway) than the obstructive type
completely abolished during the
whole event
Mixed apnea When in the same patient we have Usually, the central apnea event is
a combination of central and followed by the obstructive one
obstructive sleep apnea episodes
characterized by repeated cessation of breathing during sleeping, due mostly to

complete or partial oropharyngeal obstruction; therefore, it is a serious, potentially
life-threatening condition. OSA is usually found in severe snorers, in which there
are periods of decreased breathing or a complete cessation of breathing during
sleep due to an obstruction of airflow. The differences in the definition of OSA,
CSA, and a combination of these two (referred as “mixed apnea”) are displayed in
Table 13.2.
The term “upper airway resistance syndrome” (UARS) was coined by
Guilleminault et al. In 1993 UARS is usually defined as the presence of daytime
sleepiness associated to a sleep-disordered breathing and microarousals related to
respiratory effort (RERA) but without sufficient apneas/hypopneas episodes for
meeting the criteria for OSA. The diagnosis is based on both the association of clini-
cal symptoms and polysomnographic findings. UARS patients usually complain of
snoring associated with daytime sleepiness.
Several types of events can occur during sleep-disordered breathing (SDB) and a
detailed description of them can be found in Table 13.3.
The clinical spectrum of SDB conditions tends to progress with aging as seen on
Fig. 13.1.
Firstly, the primary snoring condition is primarily a “social” problem where no
excessive daytime sleepiness is present, and the sleep study is within normal obser-
vations. Primary snoring can be further categorized as intermittent, mild chronic,
and heavy chronic as it increases in severity.
Secondly, as for UARS, snoring and excessive daytime sleepiness are present
though sleep study is found normal.
Table 13.3 Definition of events during SDB

Type of event Definition Comment
Snoring Loud sound during sleep generated The hallmark presenting symptom of
at the level of the upper airway OSA in up to 95% of patients
and associated with the vibration Snoring alone is a poor predictor of
of the soft palate and the OSA
restriction of the air passage with The absence of it makes OSA unlikely
noisy air turbulences but doesn’t exclude it
Apnea Complete cessation or decrease in At least 90% of the event’s duration
nasal airflow by ≥90% of baseline must meet the amplitude reduction
for at least 10 s criteria for apnea
Hypopnea Decrease in nasal airflow by At least 90% of the event’s duration
≥90% of baseline for at least 10 s must meet the amplitude reduction
plus ≥4% oxygen desaturation criteria for hypopnea
from pre-event baseline
Hypopnea Decrease in nasal airflow ≥50% of At least 90% of the event’s duration
(alternative) baseline for at least 10 s plus ≥3% must meet the amplitude reduction
oxygen desaturation from criteria for hypopnea
pre-event baseline or the event is
associated with an arousal
RERA Increased respiratory effort for at REPA events are not usually associated
(respiratory least 10 s, on esophageal pressure with oxygen desaturation
effort-related recording to maintain a normal An event meeting the criteria of apnea/
arousal) airflow leading to an arousal from hypopnea cannot be a REPA.
sleep shown in the EEG recording REPA events are better detected by
esophageal manometry, but nasal
pressure and respiratory-induced
plethysmography belts can also be used
Table 13.4 Definition of OSA severity stages

Type of OSA Definition Alternative
Mild OSA AHI ≥5 and <15 in an overnight Not usually related to high oxygen
PSG study desaturation degrees
Moderate OSA AHI ≥15 and <30 in an overnight Or when the lowest oxygen saturation
PSG study is ≥50%
Severe OSA AHI ≥30 in an overnight PSG Or when the lowest oxygen saturation
study levels are <50%
Lastly, obstructive sleep apnea (OSA) is the most common condition with three
severity stages (Table 13.4) according to the apnea–hypopnea index (AHI), which is
the number of apnea and hypopnea events per hour of sleep. This condition is usu-
ally associated with:
• Profound snoring, gasping, snoring, and cessation of breathing during sleep

• Excessive daytime sleepiness
Table 13.5 Clinical differences between OSA and UARS

Clinical/PSG characteristics OSAHS UARS
Presence of daytime sleepiness Common Common
Arterial hypertension Common Uncommon
Orthostatic hypotension Uncommon Common
Allergic rhinitis Uncommon Common
Headache Uncommon Common
Irritable bowel and functional somatic Uncommon Common
syndromes
Sleep onset insomnia Uncommon Common
Mid-sleep insomnia Common Common
AHI ≥5 by definition <5 by definition
RERA events/hour of sleep <10 per hour/sleep ≥10 per hour of sleep
Lowest oxygen saturation <92% average Usually 92%
a-Delta sleep Uncommon Common
• An abnormal sleep study

• Multiple systemic effects (life-threatening potential)
More clinical differences between OSA and UARS can be found in Table 13.5,
according to polysomnography (PSG) and presence of other signs, symptoms, and
medical conditions.
13.3 Epidemiology and Etiology (Risk Factors)
Primary Snoring:
• Occurs in all age groups, but increases with age (40–60% of adults over 40 report
snoring).
• In children, it is usually related to the presence of enlarged tonsils or
adenoids.
• More prevalent in males, particularly in Hispanic, Asian, and African American.
• Three times more common in obese people.
Obstructive Sleep Apnea (OSA): Overall prevalence is 9% in females and 24% in

males
• Symptomatic OSA in 2% of females and 4% of males.

• Have signs of potential sleep-disordered breathing (SDB) since RDI >5.
• Moderate-to-severe SDB is frequent in the general population, affecting 17% of
males and 9% of females between ages 50 and 70.
Fig. 13.2 Non-modifiable and modifiable risk factors in OSA
OSA Risk Factors

Several risk factors have been described of being responsible for the develop-
ment and progression of OSA. These can be categorized as modifiable and non-
modifiable OSA risk factors and are presented in Fig. 13.2.
The critical abnormality in OSA is the repetitive complete or partial collapse of the
upper airway during sleep. Because of the relationship between form and function,
upper airway anatomy must be taken into consideration in OSA pathophysiology.
The upper airway has a collapsible segment that extends from the hard palate to the
vocal cords. Thus, the size and the shape of the upper airway will determine the prob-
ability of suffering OSA. When there is a restriction in the size of the bony compart-
ment, and excess of soft tissue around the airway or a combination of the two, there
will be an excess of extraluminal tissue pressure, producing subsequently a reduction
in the caliber and thus affecting negatively the degree of patency (Fig. 13.3).
Certain skeletal conditions as retrognathia; retro-positioning of the maxilla,
mandibular, and hypoplasia; or an inferiorly positioned hyoid bone reduce the vol-
ume of the bony compartment. In addition, deposition of fat tissue around the upper
airway as seen in obesity, macroglossia, adenotonsillar enlargement, thickening of
the lateral pharyngeal walls, enlargement of the soft palate, and edema/inflamma-
tion are among the soft tissue factors that can favor the airway collapse.
Favors PATENCY Pharyngeal dilator muscles Small airway size

Larger airway size Upper airway resistance
Larger mandible Negative inspiratory
Favors COLLAPSE
Higher lung volume pressure
Less collapsibility Smaller mandible
Greater collapsibility
Extraluminal tissue
pressure
Fig. 13.3 The unbalance between upper airway collapse and patency in OSA pathophysiology
However, the activity of the pharyngeal dilatator muscles and the central control
of the ventilation are also key factors in the pathophysiology of OSA. The impair-
ment of mechanoreceptor sensitivity, of the upper airway neuromuscular reflexes,
and of the strength and endurance of pharyngeal dilatator muscles can produce a
decrease in the pharyngeal dilator muscle activity. The dysregulation of the upper
airway neuromuscular reflexes can be a consequence from a neuro-sensorial injury
due to inflammation and trauma on the upper airway caused by snoring.
13.4.1 Systemic Effects of OSA
Obstructive sleep apnea (OSA) is a potential life-threatening condition since apnea may
trigger a cascade of primary events and physiological consequences involving dysfunc-
tions in respiratory, cardiovascular, and central nervous systems (Figs. 13.4 and 13.5).
Hence, these OSA events may lead to increased heart rate and blood pressure (hyperten-
sion), cardiovascular disease, type 2 diabetes, neurocognitive impairment, and increased
risk to suffer motor vehicle accidents. The risk of heart failure is increased by 140%, the
risk of stroke by 60%, and the risk of coronary heart disease by 30% in OSA patients.
Some community studies showed evidence that OSA is a predisposing factor for
cardiovascular mortality, independently of traditional cardiovascular risk factors.
The increase in morbidity and mortality is likely to involve intermediate pathways
that include dyslipidemia, glucose intolerance, and hypertension along with central
obesity which defines the so-called metabolic syndrome. This is the reason why
OSA is thought to contribute to the development of type 2 diabetes. Out of the two
phenotypic components of OSA, hypoxemia is the one more closely associated with
glucose intolerance and cardiovascular disease, whereas sleep microarousals are
more closely associated with incident hypertension.
Sequences of events
Primary events Physiologic consequences Clinical features
Decreased pleural pressure

Sleep onset Left heart failure
Increased cardiac afterload
Vagal bradycardia
“Unexplained” nocturnal death
Ectopic cardiac beats
Pulmonary hypertension
Pulmonary vasoconstriction
Right heart failure
Apnea
Systemic vasoconstriction Systemic hypertension
↓O2, ↑CO2, ↓pH Acute CO2 retention Chronic hypoventilation
Arousal from sleep Cerebral dysfunction Escessive daytime sleepiness

Intellectual deterioration
Loss of deep sleep Personality changes
Resumption Sleep fragmentation Behavioral disorders
of airflow
Excessive motor activity Restless sleep
Return to sleep
Fig. 13.4 Sequence of events in OSA together with their physiological consequences and associ-
ated clinical features
Upper airway Obstructive sleep

Microarousals
collapse apnea
Hypoxia and sympathetic activation
Respiratory dysfunction Nervous system

disregulation
Systemic
Pulmonary Vascular disease Worsening hypertension and
Arrhythmia and myocardial
hypertension infarction heart failure left ventricular
hypertrophy
Cardiovascular
Dysfunction
Fig. 13.5 Dysfunctional consequences of OSA in respiratory, cardiovascular, and central nervous
systems
The neurocognitive deficits associated with OSA include a decrease in vigilance,

memory, and executive function and can be a result of the effects of sleep loss in the
prefrontal cortex. Although daytime sleepiness is easily recovered after OSA treat-
ment, it seems that permanent injury to the brain’s cognitive centers is secondary to
the chronic intermittent hypoxia. Hence, incomplete recovery of those initial neuro-
cognitive deficits does occur even after an appropriate OSA treatment. It is also
important to note that in children, OSA-driven neurocognitive effects can be related
to cognitive–behavioral problems, attention-deficit/hyperactivity disorder (ADHD)
and subsequently impaired academic performance.
The diagnosis of OSA and SDB is made based on the recognition of typical clinical
signs and symptoms, the clinical examination, and the evaluation of sleep studies.
Although overnight full PSG is the gold standard for the diagnosis of OSA and sleep
disorders according to the American Academy of sleep medicine, the use of home
sleep monitors along with a comprehensive clinical evaluation may be used as an
alternative to PSG for patients who have a high pretest probability for OSA.
The suspicion of having OSA is based on the presence of clinical signs and
symptoms. Those can be divided in daytime (e.g., excessive daytime sleepiness,
restless sleep, morning headaches, neurocognitive impairment, depression) and
nighttime symptoms (e.g., snoring, choking or gasping, GERD).
The use of different questionnaires can be of help, and they are used mainly as a
screening tool to detect the presence of excessive daytime sleepiness, which is a
main finding in patients with OSA. The Epworth Sleepiness Scale (ESS) is one
example of a quantifiable subjective measure of sleepiness. In this scale, the indi-
vidual is asked to rate on a scale of 0–3 (0, no chance; 3, high likelihood) the chance
of dozing in a series of eight situations. This score has a modest correlation with
physiological measures of sleep but has a better correlation with the respiratory
disturbance index in patients with obstructive sleep apnea.
In addition, a set of four basic questions represented by the acronym STOP can
also be used. A positive response to two or more questions represents an increased
risk for sleep apnea. The expanded version, the STOP–BANG questionnaire, has
been demonstrated to highly predict sleep apnea’s presence (Table 13.6). This ques-
tionnaire can have four more questions represented by the acronym BANG. If the
score is eight, the probability for severe sleep apnea is nearly 82%.
A comprehensive clinical examination also provides the clinician with the ana-
tomical risk factors that may lead to the diagnosis of OSA. The Table 13.7 below
displays a summary of the most common physical findings and signs and symptoms
in OSA patients.
Imaging plays a role in the anatomic assessment of the airway and adjacent struc-
tures. Although imaging techniques for the head and neck are not regularly used to
diagnose OSA, the use of certain techniques can help to (1) visualize the airway, (2)
detect anatomic abnormalities, and (3) ultimately predict the risk for upper airway
obstruction that may contribute to the presence of a SBD. Thus, cephalometric analysis,
Table 13.6 STOP and BANG questionnaires
STOP questionnaires Questions Comments
S for snoring Does the patient snore Snoring is one of the

loudly? highest OSA indicators
T for tiredness Does the patient often feel Indicator of non resting
tired? sleep
O for observed Has someone observed that Witnessed apneas are

the patient´s breathing stop always a clue for suffering
durin sleep OSA
P for pressure Does the patient have high Hypertension frequently

blood pressure? associated to OSA
Bang questionnaire Comments
B for Body Mass Index BMI > 28
A for age Age > 50 years OSA increases with age
N for neck size Male ≥ 17 in; Female ≥ 16˝ Neck size is a strong
predictor of airway
collapsability
G for gender Are you a male? OSA more frequent in males
Table 13.7 Common physical findings and signs and symptoms in OSA
Obstructive sleep apnea
Common physical findings Common signs and symptoms
1. Enlarged uvula 1. Snoring
2. Soft palate hyperplasia 2. Stop breathing at night
3. Nasal congestion 3. Excessive daytime sleepiness
4. Nasal polyps 4. Morning headaches
5. Enlarged tonsils 5. Nightime gasping
6. Enlarged tongue 6. Restless sleep
7. Retruded mandible 7. Poor sleep quality
8. Receded chin 8. Irritability
9. Neck size >17" 9. Short-term memory loss
10. Overweight and obese 10. Decreased attention and concentration
11. Performance deficiencies
12. Depression
13. GERD
14. Nocturnal enuresis
15. Impotence
16. Weight gain
MRI, acoustic reflections, and computed tomography scans are used as part of the
patient comprehensive exam. Cone beam computed tomography (CBCT) scans are
becoming more and more popular in the dental field, and since these techniques include
the teeth, jaws, spine, cranial base, and facial soft tissues, they provide an excellent
opportunity to evaluate the functional and developmental relationships between these
structures. Furthermore they allow us to visualize and calculate the airway dimension.
Sleep studies are the basic diagnostic tools to provide the definite diagnosis of
SDB and OSA, where a complete collection of physiological data from the wake/
sleep stages is required for interpretation by a trained sleep medicine specialist.
The American Academy of Sleep Medicine (AASM) defined four levels of sleep
studies from which an objective-based assessment is made. These four levels are
differentiated per the number of physiological signals recorded as well as if the
sleep study is attended or not by a sleep technologist.
Type I sleep study or polysomnography (PSG) is an overnight sleep study per-
formed in a sleep center and monitored by a sleep technologist in a nearby control
room with the record and registration of at least seven physiological measures. The
PSG is considered to be the “gold standard” in sleep medicine relative to objective-
based sleep studies. In Table 13.8 a description of the different types of sleep studies
and monitors, with comments about the clinical application of each one, is showed.
Table 13.8 Types of sleep studies and monitors

Type I Type II Type III Type IV
Definition Attended PSG Unattended Modified portable Continuous single
PSG sleep apnea testing or dual
bioparameter
recorder
Signals Minimum of 7 Minimum of 7 Minimum of 4 Minimum of 1
including EEG, including EEG, including chest channel including
EOG, chin EMG, EOG, chin movement, air flow, oxygen saturation,
ECG, airflow, EMG, ECG, heart rate or ECG, airflow, or chest
respiratory effort, airflow, and oxygen movement
and oxygen respiratory effort, saturation
saturation and oxygen
saturation
Attended Yes No No No
Body position Objectively Possible Possible No
documented
Leg EMG or motion Optional Optional Optional
movements sensor desirable
but optional
Interventions Possible No No No
Clinical Diagnosis of OSA Primarily used OSA diagnosis in OSA diagnosis in
application and other for research patients with patients with
sleep-related studies moderate-to-high moderate-to-high
disorders pretest probability pretest probability
Efficacy of OSA Test efficacy of oral if monitor has ≥3
treatments (CPAP appliances channels
or appliance (controversial) Test efficacy of
titrations) Research studies oral appliances
Research studies Research studies
The treatment of snoring and OSA will depend on the severity of the disease
(particularly in OSA), and this will determine the treatment options and sequence
of care.
13.7 Treatment Options, Goals, and Sequencing of Care
This section will focus on OSA and primary snoring conditions. These are the only
conditions that can be managed by an experienced dentist in collaboration with a
sleep medicine specialist. Ideally, an effective treatment approach for OSA is to
reverse excessive daytime somnolence and fatigue, reduce the risks associated with
this condition, minimize the impact of cardiovascular effects, and improve quality
of life. In many cases the participation of other healthcare professionals such as the
ENT, pneumologists, cardiologists, and maxillofacial surgeons, among others, is
mandatory. In fact, the ideal treatment plan is to always establish different patient’s
needs depending on the severity of the apnea and other health issues related to the
patient’s condition. Below is a description of cognitive–behavioral, medical devices,
pharmacological, and surgical options for OSA management:
1. Cognitive–behavioral: We should never underestimate the importance of patient

education, especially those items addressed to have an impact on risk factors’
modification. Weight loss, changes on sleep position, smoking cessation, alcohol
and sedative drug intake avoidance, and sleep hygiene measures are included
among the most common approaches.
2. Medical devices: The most successful medical modalities for the management of
OSA are the use of positive airway pressure (PAP) devices and oral appliances:
2.1. PAP devices: The most successful medical treatment for OSA is the use of
positive airway pressure devices, which maintain upper airway patency dur-
ing sleep simply by providing a pneumatic splint. PAP devices can be deliv-
ered by continuous (CPAP), bi-level (BPAP), or auto-titrating (APAP)
modalities. CPAP supplies a flow of positive air pressure adjusted to the
level needed to keep the airway open, delivered through a facial device. It
reduces AHI, blood pressure, and cardiac arrhythmias and improves oxygen
saturation levels, sleep efficiency, self-reported sleep, and well-being. The
main disadvantage is that CPAP devices are sometimes difficult to use, thus
affecting compliance. Despite CPAP being highly efficacious in preventing
upper airway collapse, patients’ acceptance, tolerance, and adherence are
often low, thereby reducing effectiveness. Several risk factors and comorbid
conditions seem to be associated with decreased compliance, especially
depression. PAP therapy is considered the first line of treatment for those
patients suffering from moderate-to-severe OSA. The success rate with
CPAP therapy is considered around 95% of cases.
2.2. Oral appliances: In those cases where patient is intolerant to CPAP, when
the level of compliance to CPAP therapy is low, and in those cases with
primary snoring or mild-to-moderate OSA, the use of oral appliances (OAs)
should be considered. There are two main types of oral appliances: tongue
retaining devices and mandibular repositioning devices (a.k.a. mandibular
advancement devices). It is important to clarify that their level of efficacy is
always lower than the CPAP therapy.
While mandibular advancement devices (MADs) increase the anteroposterior

dimensions of the oropharynx and velopharynx by repositioning and maintaining
the lower jaw in a forward position during sleep, tongue retaining devices (TRDs)
provide a forward movement of the tongue producing more favorable changes in
the retroglossal region. Anyway the positive effect is attributed to changes in airway
configuration. Due to comfort and compliance issues, MADs are usually the first
choice unless the patient is edentulous where tongue retaining devices seem to be
the first option. There are numerous types of MAD available whose differences rely
on material of fabrication, design, advancement mechanisms, size, and thickness.
The level of efficacy of OA for the management of OSA is estimated in 76% in
cases of mild OSA (5–15 events/hour sleep), 61%i in moderate cases (15–30 events/
hour), and 40% in severe cases (more than 30 events/hour). Different studies have
shown that therapy with OA is usually more successful in younger patients and
female gender and patients with small neck, lower body mass index (BMI), and
retrognathic mandible and positional OSA cases.
The complications and side effects with the use of OA are frequent but usually
minor and temporary and include increase or decrease in salivation, tooth movement,
tooth soreness, masticatory muscles or TMJ pain, worsening in OSA (around 13% of
patients), bite discomfort, and occlusal changes (posterior open bite). There are rela-
tive contraindications for the use of OA. These are usually severe or active periodontal
disease, active TMD pathology, inadequate dentition (less than six teeth remaining),
central sleep apnea, growing children, morbid obesity, unmotivated patients, severe
hypoxemia, severe OSA, and concomitant severe cardiovascular pathology.
The use of OA in the treatment of OSA in mild-to moderate cases as well as
severe cases intolerant to CPAP therapy is recommended as the current practice
parameter. OA also can be used as a part of combination therapy with CPAP and/or
upper airway surgery. The flowchart and decision tree for the management of snoring
or OSA with a CPAP or MAS are shown in Fig. 13.6 for a better understanding.
3. Pharmacological: A large range of pharmacological approaches have been

explored over the years, but their effectiveness to treat OSA has been proved
minimal, and research is undergoing to find better options. Nasal corticosteroids
can reduce AHI index and can help with allergic nasal congestion and vasomotor
rhinitis associated with CPAP. Only modafinil (200–400 mg/day) or armodafinil
(150–250 mg/day) has shown mild-to-moderate positive effects in specific OSA
cases.
Patient snoring +/− witnessed apneas and associated symptoms
Sleep medicine physician
PSG/Home sleep testing + Comprehensive evaluation
Primary snoring Mild to moderate OSA Severe OSA
Always consider Behavioral Treatment and control of modifiable risk factors
Treatment with MAD Choice of MAD or CPAP CPAP treatment
Intolerant
to CPAP
CPAP
Treatment with MAD Treatment with MAD
Clinical Titration Clinical Titration
Polysomnography/Portable monitor
Titration of OA
Evaluation by sleep specialist or

general physician
Long term follow up

Dentist every year
General physician every 3-5 years
Fig. 13.6 Treatment algorithm for the management of primary snoring and OSA with OA
(Modified from Pliska and Almeida [34]. Permission to modify and reproduce was granted)
4. Surgical: This is only indicated in severe OSA clinical scenarios when patients
have an anatomic obstruction. There are different surgical techniques for treating
OSA, whose aim is to relieve the obstruction by removing or bypassing it or
increasing airway size. The selection of what modality to use depends on
patient’s anatomy and physiology. The selection process only comes after a full
evaluation by an ENT or a maxillofacial surgeon specialized in OSA manage-
ment. The most common surgical procedures for OSA treatment are tracheos-
tomy, tonsillectomy/adenoidectomy (for children mainly), septoplasty/turbinate
reduction, uvulopalatopharyngoplasty (UPPP), tongue base reduction, hyoid
suspension, genioglossus advancement, maxillomandibular advancement, or a
combination of these techniques.
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Part VI
Temporomandibular Disorders
and Occlusal Dysfunction
Temporomandibular Joint Disorders
14
Jeffrey P. Okeson, Cristina Perez, and James R. Fricton
Pearls of Wisdom
• Temporomandibular joint functional disorders are classified into derange-
ments of the condyle-disc complex, structural incompatibility of the artic-
ular surfaces, and inflammatory joint disorders.
• Clinical signs and symptoms may range from non-painful signs of joint
noises to acute and chronic pain and dysfunction.
• These conditions are prevalent; nevertheless, only some require treatment.
• Diagnostic criteria are described in the AAOP guidelines [1] and diagnos-
tic criteria for TMD [2].
• The clinician should always match the level of complexity of the manage-
ment program with the complexity of the patient. In complex patients, the
use of a pain clinic team to facilitate success is often needed.
• Employing clinical paradigms of self-care, education, and self-responsibility
in the patient’s care will enhance long-term outcomes and maintain positive
relationships between the patient and the clinician.
J.P. Okeson, DMD (*)

Division of Orofacial Pain, University of Kentucky College of Dentistry,
Lexington, Kentucky 40536-0297, UK
e-mail: okeson@uky.edu
C. Perez, DDS, MS
Division of Pediatric Dentistry, University of Kentucky College of Dentistry,
Lexington, Kentucky 40536-0297, UK
e-mail: cristina.perez@uky.edu
J.R. Fricton, DDS, MS, Dip. ABOP
Division of TMD and Orofacial Pain, University of Minnesota School of Dentistry,

DOI 10.1007/978-3-319-51508-3_14
146 J.P. Okeson et al.
14.1 Introduction
One major category of temporomandibular disorders relates to functional disorders

of the temporomandibular joints. They are often called internal derangements, but
this term only represents one subcategory. Functional disorders of the TMJ can be
classified into three broad categories:
1 . Derangements of the condyle-disc complex

2. Structural incompatibility of the articular surfaces
3. Inflammatory joint disorders
The first two categories have been collectively referred to as disc-interference

disorders. The term disc-interference disorder was first introduced by Welden Bell
[3] to describe a category of functional disorders that arise from problems with the
condyle-disc complex. Some of these problems are due to a derangement or altera-
tion of the ligaments that attach the disc to the condyle; others to an incompatibility
between the articular surfaces of the condyle, disc, and fossa; and still others to the
fact that relatively normal structures have been extended beyond their normal range
of movement. Although these broad categories have similar clinical presentations,
they are treated quite differently. It is therefore important that they be differentiated.
Inflammatory disorders may arise from any localized response of the tissues that
make up the TMJ. They are often the result of chronic and sometimes progressive
disc derangement disorders. The two major symptoms associated to functional TMJ
disorders are pain and dysfunction.
These three broad categories are described below in detail:
14.1.1 Derangements of the Condyle-Disc Complex
These disorders present as a range of conditions that relate to the functional rela-
tionship between the articular disc and the condyle. Under normal conditions the
disc is attached to the condyle by the medial and lateral collateral ligaments. These
attachments allow the disc to rotate anteriorly and posteriorly on the condyle as the
condyle translates out of the fossae (Fig. 14.1).
If the morphology of the disc is altered and/or the discal ligaments become elon-
gated, the disc is then permitted to slide (translate) across the articular surface of the
condyle. This type of movement is not present in the healthy joint. When this occurs
the disc can become displaced from its normal position and thus this is known as a
disc displacement [4]. When a disc displacement is present, opening the mouth will
bring the condyle forward to a more stable position on the disc, and an unusual
movement can occur between the condyle and disc resulting in a joint sound (click).
With time and further elongation of the ligaments, the disc can gain more freedom
to move (translate) between the condyle and fossae.
Eventually, the disc can be forced through the discal space, collapsing the joint
space behind. When this occurs, inter-articular pressure will collapse the discal
space, trapping the disc in the forward position. Then, the next full translation of the
condyle is inhibited by the anterior and medial positioning of the disc. The person
14 Temporomandibular Joint Disorders 147
Fig. 14.1 Normal condyle and disc movement during opening of the mouth. Note: The disc
always remains between the condyle and fossa, but it also rotates posteriorly on the condyle during
the opening movement (From Okeson [15])
a b
Fig. 14.2 The articular disc is displaced anterior to condyle in the normal closed mouth position
(a). During opening (b) the condyle pushes the disc forward until it is reduced into its normal posi-
tion (c). This condition is called a disc dislocation with reduction (From Okeson [15])
feels the joint being locked in a limited closed position [5]. Since the articular sur-
faces of the disc have actually been separated from the condyle, this condition is
referred to as a dislocation of the disc.
Some individuals with dislocation of the disc are able to move the mandible in
various lateral or protrusive directions to accommodate the movement of the con-
dyle over the posterior border of the disc, and the locked condition is resolved. If the
lock occurs only occasionally and the person can resolve it with no assistance, it is
referred to as a dislocation with reduction (Fig. 14.2).
a b
Fig. 14.3 The articular disc is displaced anterior to condyle in the normal closed mouth position
(a). During opening (b) the condyle pushes the disc forward; however, the disc is never reduced
into its normal position (c). This condition is called as a “disc dislocation without reduction.”
Since this condition often limits full opening of the mouth, it is often referred to as a “closed lock”
(From Okeson [15])
The next stage of disc derangement is known as disc dislocation without reduc-
tion. This condition occurs when the person is unable to accommodate the condyle
to return the dislocated disc to its normal position on the condyle. The mouth cannot
be opened maximally because the position of the disc does not allow full translation
of the condyle (Fig. 14.3).
14.1.2 Structural Incompatibility of the Articular Surfaces
Some disc derangement disorders result from problems between the articular sur-
faces of the joints. In a healthy joint, the articular surfaces are firm and smooth and
when lubricated with synovial fluid move almost without friction against each other.
However, if these surfaces become altered by trauma or inflammation, movement can
be impaired. As a result Adhesions and Adherences can form. Adherences are consid-
ered to be a temporary sticking of the articular surfaces, while adhesions are more
permanent. Disc perforations are another form of structural incompatibility [6].
In some individuals, clinical observations of full mouth opening reveals a
momentary pause, followed by a sudden jump or leap to the maximally open posi-
tion. This jump does not produce a clicking sound but instead is accompanied by
more of a thud. This condition is called subluxation or hypermobility [7].
On occasion the mouth is opened beyond its normal limit and the mandible locks.
This is called spontaneous dislocation or an open lock. It should not be confused
with the closed lock, which occurs with a functionally dislocated disc without
reduction. With spontaneous dislocation the patient cannot close the mouth. This
condition is almost always produced by wide opening, for example, an extended

yawn or a long dental procedure. Open lock can be produced when the disc and the
condyle as a whole translate past the eminence and when trying to return the poste-
rior thicker part of the disc does not permit its return.
14.1.3 Inflammatory Joint Disorders
Inflammatory joint disorders are a group of disorders in which various tissues that
make up the joint structure become inflamed as a result of an insult or breakdown.
Any or all of the joint structures may be involved. Disorders that form part of this
category are synovitis, capsulitis, retrodiscitis, and the arthritides. Synovitis and
capsulitis are characterized by inflammation of the synovial tissues and the joint
capsule. These disorders are often mentioned together due to the difficulty in sepa-
rating them clinically. Retrodiscitis results from an encroachment of retrodiscal tis-
sues by the condyle due to an altered forward position of the disc.
Joint arthritides represent a group of disorders in which destructive bony
changes are seen. One of the most common types of TMJ arthritide is called osteo-
arthritis (also known as degenerative joint disease). Osteoarthritis represents a
destructive process by which the bony articular surfaces of the condyle and fossa
become altered. It is generally considered to be the body’s response to increased
loading of a joint [8]. There are certainly other types of arthritides that can affect
the TMJs. Many of these are considered polyarthritides such as traumatic arthritis,
infectious arthritis, rheumatoid arthritis, gout, psoriatic arthritis, and ankylosing
spondylitis.
Many of the common joint disorders present as non-painful conditions with clinical
symptoms that include joint sounds, deviation of the jaw on opening, or limitation
of opening. However, on occasion pain and dysfunction are present in which the
following clinical findings are common:
• Pain: Common sites of pain in the temporomandibular joint include preauricular

pain, earache, jaw pain, facial pain, and temple/parietal headaches. Pain can be
acute or chronic and present as a constant steady dull ache that fluctuates in
intensity or acutely sharp and only associated to movement. Duration may vary
from hours to days.
• Joint tenderness: In arthralgia, the tenderness is reported as deep and localized
on the lateral or posterior aspects of the joint capsule.
• Limited or deviation in range of motion: With disc displacement and disc dislo-
cation with reduction, mandibular deviation may be seen at the point of the joint
sound, but normal range of movement is usually achieved. With disc dislocation
without reduction, gross limitation of opening is often seen (<30 mm), especially
when the disorder is acute.
• Joint sounds: Joint sounds alone are not diagnostic of joint pathology. However,
specific types of sounds couple with clinical signs, in these cases imaging, may
be helpful to make a diagnosis. These may include reciprocal clicking (both
opening and closing) associated with disc displacement and disc dislocation with
reduction. Non-reproducible opening or closing clicks or fine crepitus may occur
with later stages of disc dislocation. Coarse crepitus may occur with osteoarthri-
tis or osteoarthrosis.
• Other associated signs and symptoms: These would include occlusal changes
such as an anterior open bite with loss of condylar height or posterior open bites
associated with anterior condylar displacement with inflammation or tumors.
Pain is increased with movement of the joint and occasionally otologic symp-
toms such as tinnitus, and plugged ears may be present.
14.3.1 Prevalence
Temporomandibular joint disorders are a common cause of pain and dysfunction in

the masticatory system affecting up to 25–30% of the general population with about
5% having symptoms severe enough to warrant treatment [9]. The prevalence of
osteoarthritis in the TMJ is significantly less.
14.3.2 Comorbid Conditions and Complicating Factors
• Osteoarthritis, rheumatoid arthritis, and other systemic rheumatological or con-

nective tissue conditions
• Fibromyalgia, myofascial pain, and muscle pain in the jaw and other parts of the
body
• Malocclusion and occlusal dysfunction
• If chronic, medication dependencies, disuse, and psychological factors such as
emotional difficulties or pain behaviors
14.3.3 Etiologic Factors
• Direct macrotrauma to the joint through direct blow or opening the mouth too
wide or for too long a period during activities such as dental visits, eating, yawn-
ing, and sexual activity.
• Indirect trauma due to whiplash type of injury in some cases may be an initiating
factor.
• Occupational and repetitive strain injury may contribute to joint pain.
• Microtrauma to the TM joint produced by oral parafunctional muscle tension pro-

duced by habits such as teeth clenching, jaw thrust, gum chewing, and jaw tensing.
• Poor positioning of the head, neck, or tongue.
• Gross occlusal instability.
• Psychosocial stressors such as relationship conflicts, monetary problems, feeling
hurried, over scheduled, and poor pacing skills can play an indirect role in rein-
forcing chronic pain.
14.4.1 Biomechanical Strain Hypothesis
The genesis of disc disorders and TMJ arthralgia has been at least partially attrib-
uted to abnormal biomechanical forces on the condyle. These alter the shape, form,
and function of articular tissues. Friction due to abnormal jaw function and malposi-
tion of the disc may exacerbate both jaw displacement and changes to the form and
function of the disc. In other cases, a blow to the jaw, inadvertent biting of a hard
object, or excessive chewing may be inciting factors. Occasionally, whiplash injury
may indirectly contribute to biomechanical trauma.
14.4.2 Molecular and Cellular Hypothesis
Multiple cellular and molecular mechanisms are also involved in initiation and pro-
gression of degenerative joint disease because they modify the adaptive capacity of
the joint. Trauma and mechanical stresses may release free radicals such as free iron
and directly or indirectly damage cellular components and play a role in TMJ adhe-
sion formation through oxidative modification of proteins and the formation of
intramolecular and intermolecular cross-linking of fibrinogen and fibronectin [10].
Inflammatory mediators including cytokines, TNF-α, and IL-1 are expressed and
produce large amounts of matrix metalloproteinases (MMPs), which in turn degrade
extracellular matrix components including collagens and proteoglycans. The
increase in arachidonic acid metabolism and extracellular matrix degradation lead
to deformation of the disc-condyle apparatus. There are also neurogenic contribu-
tions to pain and modulation of cell adhesion in the inflammatory state.
14.5 Diagnostic Criteria
The diagnostic criteria for each TMJ disorder has been described in two documents:
the AAOP guidelines [1] and Diagnostic Criteria for Temporomandibular Disorders
DCTMD [2]. They are summarized below:
14.5.1 TMJ Disc Displacement/Dislocation with Reduction
1. Reproducible joint noise that occurs usually at variable positions during opening
and closing mandibular movements.
2. Soft tissue imaging reveals displaced disc that improves its position during jaw
opening, and hard tissue imaging shows an absence of extensive degenerative
bone changes.
3. Any of the following may accompany the above:
• Pain, when present, is precipitated by joint movement.
• Deviation of the mandible during movement coinciding with a click.
• No restriction in mandibular movement.
• Episodic and momentary catching of smooth jaw movement during mouth
opening (<35 mm) that self-reduces with voluntary mandibular repositioning.
14.5.2 TMJ Acute Disc Dislocation Without Reduction
1. Persistent marked limited mouth opening (<35 mm) with history of sudden

onset.
2. Deflection to the affected side on mouth opening.
3. Marked limited laterotrusion to the contralateral side (if unilateral disorder).
4. Soft tissue imaging reveals displaced disc without reduction, and hard tissue
imaging reveals no extensive osteoarthritic changes.
• Pain precipitated by forced mouth opening
• History of clicking that ceased with the locking
• Pain with palpation of the affected joint
• Ipsilateral hyperocclusion
• Moderate osteoarthritic changes with hard tissue imaging
14.5.3 Chronic TMJ Disc Dislocation Without Reduction
1. History of sudden onset of limited mouth opening that occurred more than
4 months ago.
2. Soft tissue imaging reveals displaced disc without reduction, and hard tissue
imaging reveals no extensive osteoarthritic changes.
• Pain, when present, is markedly reduced from acute stage and usually pres-
ents only as a feeling of stiffness.
• History of clicking that resolved with sudden onset of the locking.
• Moderate osteoarthritic changes with imaging of hard tissues.
• Gradual resolution of limited mouth opening.
14.5.4 Spontaneous Dislocation of the TMJ
1 . Inability to close the mouth without a specific manipulative maneuver.

2. Radiographic evidence reveals condyle well beyond the eminence.
3. Pain at time of dislocation with mild residual pain after the episode.
Differential diagnosis: condyle fracture secondary to trauma
14.5.5 Synovitis, Capsulitis, and Retrodiscitis
1 . Localized TMJ pain exacerbated by function.

2. Tenderness to superior or posterior joint loading and palpation.
3. No extensive osteoarthritic changes with hard tissue imaging.
4. The following may accompany the above:
• Limited range of motion secondary to pain.
• Fluctuating swelling (due to effusion) that decreases ability to occlude on
ipsilateral posterior teeth.
• A hyperintense MRI signal when fluid is present (T2 weighting).
• Ear or preauricular pain.
Differential diagnosis: osteoarthritis, polyarthritis, ear infection, and neoplasia
14.5.6 TMJ Osteoarthritis
1 . TMJ pain at rest and with function.

2. Joint tenderness on palpation.
3. Radiographic evidence of structural bony change (subchondral sclerosis, osteo-
phytic formation, erosion) and joint space narrowing.
4. The following may accompany the above:
• Limited range of motion, deviation to the affected side
• Crepitus or multiple joint noises
Differential diagnosis: inflammation, polyarthritis, and neoplasia
14.5.6.1 Diagnostic Tests

1. Imaging studies that may be useful for TMJ functional disorders include:
• Magnetic resonance imaging (MRI) scans to view disc position
• CT scans and tomography to view structural joint pathology and degenerative
joint disease
• Panoramic radiographs to view dental, maxillary, and mandibular pathology
2. Lab studies: blood and urine studies are generally normal unless caused by a
concomitant disorder.
3. Psychometric tests: the DC/TMD axis II, Beck Depression Inventory, and SCL-
90 can help identify specific psychosocial contributing factors.
Some general considerations in the management of TMJ disorders are as follows:
• Treatment should be directed toward rehabilitating the joint, improving range of

motion, reducing tenderness and inflammation, and reducing contributing
factors.
• Treatment should attempt to reduce biomechanical strain to the joint from repeti-
tive straining activities, poor postural activities, and sustained muscle activity,
which should encourage healing.
• Treatment should attempt to inhibit peripheral and central neural input through vari-
ous treatment modalities such as cold, heat, analgesic/anti-inflammatory medica-
tions, massage, trigger point injections, and transcutaneous electrical stimulation.
• Treatment should attempt to reduce factors that facilitate continued sustained
central and peripheral neural activity such as reduction of clenching, joint trauma,
and CNS alterations such as depression.
14.7.1 Self-Care
• Most acute symptoms are self-limited and resolve with minimal intervention.
• Initial treatment should be a self-care program to reduce repetitive strain of the
masticatory system and encourage relaxation and healing of the joint and muscles.
• This includes jaw exercises, habit change, and gentle use of the jaw.
• Most patients respond well to self-care in 4–6 weeks. If symptoms do not resolve,
further assessment and treatment are indicated [11].
• Nonsteroidal anti-inflammatory drugs (NSAIDs)

• Precaution: gastrointestinal side effects. Gastrointestinal safety of COX-2 inhibi-
tors may be greater than that of nonselective NSAIDs, but recent evidence of
increased cardiovascular disease needs to be considered. Examples include:
–– Naproxen, 250–500 mg BID with meals
–– Ibuprofen, 400–800 mg TID with meals
–– Celecoxib, 100–200 mg BID
• Muscle relaxants for muscle spasm, muscle tension, nocturnal bruxism, and
improving sleep. Common side effects are sedation, dizziness, dry mouth, and, if
allergy, rash.
–– Cyclobenzaprine, 10–20 mg HS
–– Tizanidine, 4 mg HS or BID
–– Methocarbamol, 500–750 mg QID
–– Metaxalone, 400–800 mg TID
• Benzodiazepines are useful to manage anxiety. However, if used daily, depen-

dency is likely to occur. Examples include:
–– Clonazepam, 0.5–1.0 mg HS
–– Diazepam, 5 mg HS or BID
14.7.3 Physical Rehabilitation Medicine Procedures
Certain physical medicine procedures can be efficacious for patients with TMJ
restriction and pain as well as for other TMD symptoms.
• Jaw exercise is the primary and often the only physical medicine treatment required:
–– Relaxation
–– Rotation and arthrokinematics
–– Stretching (range of motion)
–– Isometric and strengthening exercise
–– Postural exercise
• Physical modalities can reduce jaw pain and increase range of motion, thereby
allowing jaw exercises to more effectively proceed. These can be particularly
helpful with muscle spasm and contracture.
–– Thermotherapy
–– Coolant therapy
–– Ultrasound
–– Phonophoresis
–– Iontophoresis
–– Electrogalvanic stimulation therapy
–– Transcutaneous stimulation therapy (TENS)
–– Laser
14.7.4 Orthopedic Intraoral Splints
These appliances can allow protection of the joint and reduce oral habits [12]. There
are three major types of splints:
• Stabilization splint: to allow passive protection of the jaw and reduction of oral
habits. Full arch occlusal contacts on flat surface with mild anterior tooth disoc-
clusion is most scientifically supported. These can be made for the maxillary or
mandibular arch.
• Anterior positioning splint: can be efficacious for painful TMJ disc displacement
or dislocation with reduction associated with reciprocal clicking and/or intermit-
tent jaw locking, especially upon awakening. Recommended for short-term,
part-time use, primarily during sleep, because they can cause occlusal changes if
worn continuously [14].
• Partial coverage splint: may cause occlusal changes in some patients. Splints
should cover all of the mandibular or maxillary teeth to prevent supraeruption of
unopposed teeth.
14.7.5 Cognitive-Behavioral Therapy (CBT)
• CBT approaches can help change maladaptive habits and behaviors that contrib-
ute to strain placed on the joint such as jaw tensing, teeth clenching, and teeth
grinding [13].
• Although many simple habits are easily abandoned when the patient becomes aware
of them, changing persistent habits requires a structured program that is facilitated
by a clinician trained in behavioral strategies. Habits do not change themselves.
Patients are responsible for initiating and maintaining behavior changes.
• Habit reversal can be accomplished by (1) becoming more aware of the habit, (2)
knowing how to correct it (i.e., what to do with the teeth and tongue), and (3)
knowing why to correct it, combined with the patient’s commitment to conscien-
tious self-monitoring and a focus upon the goal. Correcting it during the day will
help reduce it at night.
• Supplement with additional behavioral strategies such as biofeedback, medita-
tion, stress management, or relaxation techniques.
• Address poor pacing or hurrying related to a day overloaded with commitments.
• Address depression, anxiety, and other emotional problems through psychologi-
cal therapy and medications.
• Address sleep disorders (e.g., snoring, obstructive sleep apnea – discussed in
Chap. 12) with sleep hygiene self-care, medications, and if needed a sleep labo-
ratory evaluation.
14.7.6 TMJ Surgery
• If persistent pain is localized in the TMJ and is associated with specific structural
changes in the joint, surgical intervention can be considered if comprehensive
nonsurgical care is unsuccessful.
• Muscle pain and associated contributing factors should be addressed and con-
trolled prior to TMJ surgery.
• In general, the less invasive surgeries are as efficacious as those that are more
invasive, so the health-care provider should consider an arthrocentesis or
arthroscopic procedure before more invasive interventions such as discectomy,
discal repair, or complete TM joint replacement.
• Postoperative management includes appropriate medications, physical therapy, splint
therapy when indicated, and continued psychological treatment as appropriate.
14.8 Sequence of Care
• Treatment goals include:

1. Reduce or eliminate pain
2. Restore normal jaw function
3. Reduce the need for future health care
4. Restore normal lifestyle functioning
• Short-term strategy is to restore the joint to normal function, obtaining full range
of motion. Jaw exercises can help achieve this goal.
• Long-term strategy includes reducing the symptoms and their negative effects
while helping the patient return to normal function without the need for future
health care.
• Acute cases of recent onset can often be managed with palliative self-care strate-
gies designed to protect the joint and encourage healing.
• Behavioral and psychosocial evaluation should be conducted on all patients with
persistent pain to determine complexity and contributing factors.
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Temporomandibular Muscle Disorders
15
Edward F. Wright
Pearls of Wisdom
• Diagnosing and treating temporomandibular muscle disorders is a chal-
lenging yet very rewarding venture. It requires carefully listening to
patients so as to obtain a thorough history and identify potential contribut-
ing factors. An in-depth clinical exam confirms or refutes the suspicious
structures contributing to the temporomandibular muscle disorder.
• Identifying and reducing the contributing factors is the key to developing
the most cost-effective long-term management for patients with temporo-
mandibular muscle disorders.
• With the patients’ participation, methodically develop the most cost-
effective treatment plan, focusing upon each patient’s identified contribu-
tors. TMD self-management and education are the foundation for
empowering self-reliance and enhancing a positive patient to practitioner
relationship.
• Treatment often involves enlisting the help of other practitioners who pro-
vide therapies that are outside of the dentist’s realm of treatment, e.g.,
physical therapist and psychologist.
• As treatments are implemented, ensure the patient’s temporomandibular
muscle pain is sufficiently reduced and the masticatory function is restored.
• Patients are not passive recipients of our therapies but are active partners in
obtaining and maintaining their treatment goals.
E.F. Wright, DDS, MS, MAGD

Department of Comprehensive Dentistry, University of Texas Health Science Center –
San Antonio, San Antonio, TX, USA
e-mail: WrightE2@uthscsa.edu

DOI 10.1007/978-3-319-51508-3_15
160 E.F. Wright
Temporomandibular muscle disorders (TMD) are the most common cause for
patients’ temporomandibular pain, and they may coexist with temporomandibular
joint disorders (see Chap. 14). They are characterized by pain arising from dys-
functional processes within the masticatory muscles and not from the joint itself.
There are a number of muscle disorders that may occur among the masticatory
muscles including myalgia, myofascial pain with referral, myositis, and spasm
(Tab. 15.1) [1].
Myalgia is the most common masticatory muscle disorder and is diagnosed when
the patient’s muscle pain is aggravated by mandibular movement, function, or para-
function; and the patient’s pain is reproduced by palpating the painful muscle [1].
Myofascial pain with referral is a subcategory of myalgia in which, through
central processes (e.g., sensitization and convergence), patients perceive their
muscle pain in a distant location. Many dentists have observed patients
Myalgia: repetitive strain

Generally a dull aching pain in the masseter and/or temporalis muscle region that is
aggravated by mandibular movement, function, or parafunction; and the patient's pain is
reproduced by palpating the painful muscle.
Myofascial pain with referral: muscle pain perceived in a distant location from the
source
Generally a dull aching pain in a location where there is no pathology and this pain can
be reproduced by firmly palpating a tender region within a muscle at a distant location
(e.g., tooth pain caused by referred pain from the masseter muscle).
Spasm: acute onset of contracted muscle

Acute onset of a continuously contracted muscle causing constant muscle pain with a
significantly limited range-of-motion. If due to a closure muscle (masseter, temporalis, or
medial pterygoid muscle), the patient will have a limited opening. If due to a lateral
pterygoid muscle, the patient will have increased pain when trying to occlude into
maximum intercuspation and will have a limited ability to translate the ipsilateral condyle
causing a limited mandibular movement to the contralateral side. The involved muscle is
generally exquisitely tender.
Myositis: acute onset of infection or injury

Acute onset of constant muscle pain with a significantly limited range-of-motion and has
clinical characteristics of an infection, or the muscle pain is secondary to trauma to the
muscle.
Tab. 15.1 Diagnostic criteria for temporomandibular muscle disorders

15 Temporomandibular Muscle Disorders 161
complaining of tooth pain when there is no pathology associated with the teeth.
This tooth pain may be due to referred pain from a masticatory muscle, sug-
gested by reproduction of the tooth pain by firm palpation of tender regions
within a masticatory muscle and ruling out other potential sources (e.g., sinus
congestion) [1].
Spasm is an immediate onset of a constant muscle contraction causing pain and
limited range of motion [1]. Most of us can relate to this disorder by the spasm that
has occurred in our calf muscle that awoke us in the middle of the night. This disor-
der may develop within any of the masticatory muscles, but it most commonly
occurs with the lateral pterygoid muscle or the medial pterygoid muscle following
an inferior alveolar injection [2, 3].
Myositis is another acute disorder in which the muscle has clinical characteris-
tics of an infection (e.g., edema, erythema, and/or increased temperature) or inflam-
mation, in addition to meeting the criteria for myalgia. The onset of the patient’s
symptoms is directly related to an infection or trauma to the muscle [1].
Patients with temporomandibular muscle disorders generally complain of pain in

the masseter and/or temporalis muscle region. This pain is most commonly a con-
stant dull ache with an intensity that generally fluctuates with function (e.g., eating),
parafunction (e.g., clenching teeth), activities (e.g., holding tension in muscles and
resting chin in one’s hand), and stress. The pain may last for minutes, hours, or be
constant; this may be an acute or chronic disorder [4, 5].
Patients may also have various associated pain complaints, the most common
being tooth pain where there is no dental pathology and neck pain [1, 3]. The tooth
pain may be from localized inflammation from heavy clenching activities or referred
pain from the masticatory structures (e.g., myofascial pain with referral). The neck
pain may be due to a disorder within the cervical structures and/or secondary to the
TMD disorder. There are many other potential symptoms that can occur secondary
to the TMD disorder, e.g., otologic symptoms (i.e., tinnitus, ear pain, etc.) and neu-
rologic deficits due to nerve entrapment [4, 6].
Palpation of the painful muscles reproduces the patient’s pain, and these painful
muscles will generally not elongate to their normal length. If this involves a closure
muscle (masseter, temporalis, or medial pterygoid muscle), this will manifest as a
limited range of motion (less than 40 mm). Myalgia and myofascial pain with refer-
ral generally cause a slight limitation (10–20%), while myositis and spasm may
cause a gross limitation (50% or more).
162 E.F. Wright
Temporomandibular disorder (affecting muscles and the joint), or TMD, is one of

the most prevalent of all musculoskeletal disorders, with approximately 25–33% of
the general population having some TMD symptoms and 3.6–7% having it with
sufficient severity to desire treatment [1, 7]. Women request TMD treatment more
often than do men, and their symptoms are less likely to resolve than for men [7, 8].
These TMD severe muscle symptoms significantly correlate with masticatory
muscle tension, tooth clenching, grinding, and other oral parafunctional habits [5, 9].
They are also significantly correlated with an increase in psychosocial factors (e.g.,
worry, stress, irritation, frustration, and depression), and patients with poor psycho-
social adaptation have significantly greater TMD improvement when the dentist’s
TMD therapy is combined with cognitive-behavioral intervention [7, 8].
There are no specific anatomical changes within the muscle that account for tem-
poromandibular muscle pain, and there is currently no consensus on the specific
pathophysiology for this pain. Some authors speculate the pain is secondary to
vasoconstriction of arteries from repetitive muscle strain. This forms an ischemic
region that accumulates metabolic waste products, causing the release of algogenic
substances, and the muscle pain develops. It is also known that temporomandibular
muscle pain is greatly influenced by central mechanisms, e.g., phasic modulation of
excitatory and inhibitory tonic muscular input, convergence of multiple afferent
inputs, and inhibition or facilitation of central input [4, 10].
• The diagnosis is based upon the patient’s history, symptomatology, and clinical
evaluation (see Tab. 15.1). The suspected offending muscle(s) is palpated to
ensure aggravation of this muscle can reproduce the patient’s pain [3, 7]. These
palpations are performed by starting with light force and increasing the force
until the patient’s pain is aggravated or reproduced, or the force reaches 0.5–1 kg
(recommended force varies with the muscle according to the new diagnostic cri-
teria for TMD) [11].
• Blood, urine, and imaging studies are usually normal for these muscle disorders [4].
• A TMD questionnaire is often helpful to identify the contributing factors (e.g.,
daytime clenching) and rule out other potential contributors (e.g., similar muscle
pain throughout the body) [7].
• Myalgia is by far the most common cause for temporomandibular muscle pain.
Some patients will awake with the muscle pain that resolves within an hour.
Other patients will awake without symptoms, and the muscle pain develops as
the day progresses, while other patients will have constant pain that generally has
some daily variation of the pain intensity.
• The most cost-effective therapy for the long-term management of myalgia is
through identifying and satisfactorily reducing the contributing factors [4, 7].
The most common contributing factors are nighttime and/or daytime masticatory
parafunctional activity and other masticatory habits (including holding tension in
the muscles) [3, 12].
• Nighttime masticatory parafunctional activity and habits predominately contrib-
ute to patients’ pain upon awaking, and daytime habits predominately contribute
to the pain that occurs later in the day. Some treatments are more effective for the
various times of the day in which these habits occur, so the daily symptom pat-
tern helps in selecting the most effective therapies for each patient. A way to
determine this is to ask patients what is their average pain intensity (on a 0–10
scale, where 0 is no pain, and 10 is the worst pain imaginable) upon awaking and
later in the day [7, 12].
• Other pain in the region tends to cause the masticatory muscles to tighten in
response to this pain and may cause referred pain to the masticatory mus-
cles. So these potential sources (e.g., sinus, tooth, and cervical pain) for the
masticatory muscle pain must be investigated and treated if contributing to
the masticatory muscle pain. Heavy snoring or sleep apnea may also cause
patients to awake with myalgia, so this disorder should also be considered
as a potential cause or contributor for patients’ temporomandibular muscle
pain.
There are great variations in the severity and complexity with which patients pres-
ent. There are also considerable variations as to which therapies patients are recep-
tive to receiving and the degree of relief they would consider to be sufficient; these
are often related to personal finances and insurance coverage.
The recommended treatments for each diagnostic muscle subtypes will vary, but
in general, nearly all patients who are diagnosed with a temporomandibular muscle
disorder would benefit from the TMD self-management therapies (Tab. 15.2), and
this should be one of the first therapies provided.
164 E.F. Wright
1. Massage your painful muscles.

2. Apply heat, ice, or a combination to the painful muscles. Use which ever
provides the greatest amount of relief; most patients prefer heat.
3. Do not chew gum, eat hard foods (e.g., raw carrots), or eat chewy foods (e.g.,
caramels, steak, and bagels); and cut large pieces of food into small pieces.
4. Limit daily caffeine consumption to 1 regular cup of coffee, 2 cups of tea, or 1 can
of soda.
5. Keep your jaw muscles relaxed throughout the day so your teeth do not touch; do
not clench your teeth or hold tension in your jaw muscles. Ask for a coach to
help, if one is desired.
6. Eliminate other habits that could put unnecessary strain on your jaw muscles
(e.g., tapping your teeth together; resting your jaw on your hand; biting your
cheeks, lips, finger nails, cuticles, or any other objects you may put in your
mouth; pushing your tongue against your teeth; and holding your jaw in an
uncomfortable or tense position).
7. Sleep on your side or your back; do not sleep on your stomach.
8. Restrain from opening your mouth wide (e.g., yawning, yelling, and eating large
pieces of food).
9. Use over-the-counter therapies as needed:
- Apply topical creams/gels/patches containing NSAIDS over the painful areas
- Take tablets/caplets per os: naproxen, ibuprofen, acetaminophen, etc.
Tab. 15.2 TMD self-management therapies
15.7.1 Myalgia
The various contributing factors (e.g., nighttime activity, daytime activity, neck
pain, and sinus pain) are identified through patients’ history and clinical exam. The
recommended myalgia therapies will vary with the contributors, e.g., nighttime
activity, daytime activity, or a combination of these; patients with non-masticatory
contributors are generally referred to other providers who can best treat them [3, 4].
The therapies that have been suggested to be effective for awaking TMD symp-
toms are as follows: improve sleep position, wear a flat stabilization appliance at
night, take medications that decrease nocturnal EMG activity, wear a soft appli-
ance to oppose a hard appliance, and perform a relaxation session just prior to
going to sleep (Tab. 15.3). The author treats the nighttime contributors by recom-
mending these therapies to his patients in this order in addition to applicable thera-
pies in Tab. 15.5.
Stomach sleeping tends to aggravate the masticatory and cervical musculoskel-
etal systems, so recommend patients change their sleep posture to sleeping on one
or both of their sides and/or on their back. If this and the rest of the TMD self-
management instructions do not provide adequate symptom relief, provide a flat
stabilization appliance for the patient to wear at night.
1. Improve sleep positions

2. Wear a flat stabilization appliance at night
3. Take medications that decrease nocturnal EMG activity, e.g., gabapentin, amitripty line,
nortriptyline, or cyclobenzaprine
4. Wear a soft appliance to oppose a hard appliance
5. Perform a relaxation session just prior to going to sleep; this may require referring
the patient to a psychologist to train the patient how to perform this session.
6. Awaking headache can be present and may be related to snoring or sleep apnea
Tab. 15.3 Therapies primarily for awaking TMD symptoms (provided in this order)
There are a variety of medications that can help reduce the symptoms with which
patients awake. A recent study revealed that 200–300 mg of gabapentin taken at
bedtime will reduce the nighttime muscle activity similar to a stabilization appli-
ance [13]. Clinically, this has been observed to be effective for the more healthy
patients who are not taking a large number of medications.
Other medications that are often prescribed for this contributor are the tricyclic
antidepressants (for long-term use) or Flexeril (for short-term use). For the tricyclic
antidepressants, the author prescribes either 10 mg tablets of amitriptyline or nor-
triptyline (causes less drowsiness than amitriptyline) and asks patients to start with
one table near bedtime and slowly increase the dose (up to five tablets) and titrate to
the dose that provides satisfactory relief with minimal side effects. For short-term
interventions, the author generally prescribes 5 mg tablets of Flexeril and asks
patients to take one to two tablets at bedtime; many other muscle relaxants appear
to provide a similar effect.
If these therapies do not provide adequate symptom improvement, the patient
could be provided an opposing soft appliance that occludes with the hard flat stabi-
lization appliance. One study provided patients, who had not obtained adequate
improvement from wearing a flat stabilization appliance at night, an opposing soft
appliance occluding with the hard appliance. They found that patients obtained a
significant decrease in their TMD symptoms; 63% rated it as good TMD symptom
improvement and 12% rated it as some improvement [14].
If the patient has not obtained adequate awaking symptom relief, it has been sug-
gested that the patient may find benefit from performing a relaxation session just
prior to going to sleep; some patients may need a psychologist to help the patient
perform this. Providers must keep in mind that awaking myalgia may be from heavy
snoring or sleep apnea, which should have been ruled out during the initial patient
evaluation.
The therapies that have been suggested to be effective for daytime TMD symp-
toms are breaking daytime parafunctional and muscle-tensing habits; use relax-
ation, stress management, and/or biofeedback; wear a flat stabilization appliance
166 E.F. Wright
• Break daytime parafunctional and muscle-tensing habits

• Use relaxation, stress management, and/or biofeedback
• Wear a flat stabilization appliance during the day as a temporary crutch until the
patient can satisfactorily decrease the daytime habits and/or to facilitate cognitive
awareness for breaking the daytime habits
• Take a tricyclic antidepressant that causes minimal drowsiness (e.g., desipramine)
Tab. 15.4 Therapies primarily for daytime TMD symptoms (selection varies with each patient)
• Use medications, i.e., topical or oral NSAIDs, muscle relaxants, tricyclic

antidepressants, etc.
• Use physiotherapy (i.e., heat, ice, ultrasound, iontophoresis, etc.); they may be
provided by the patient at home or by a physical therapist
• Perform masticatory and/or cervical exercises provided by the dentist and/or
physical therapist
• Therapies provided to relieve neck pain
Tab. 15.5 Additional therapies beneficial for both symptom patterns (selection will vary with
each patient)
during the day; and take a tricyclic antidepressant that causes minimal drowsiness
(Tab. 15.4). The order in which these are provided will vary with the patient’s
desires; applicable therapies in Tab. 15.5 are also provided.
Symptoms that occur during the day are generally secondary to daytime habits.
The TMD self-management therapies requested that patients work to keep their jaw
muscles relaxed throughout the day so their teeth do not touch and to not clench
their teeth. If patients are unable to satisfactorily relax their masticatory muscles or
break this habit on their own, they may desire a “coach” to help them. Some psy-
chologists have training and experience with this and generally use relaxation, stress
management, and/or biofeedback to achieve this goal.
Another treatment beneficial for daytime pain is to wear a flat stabilization appli-
ance during the day. Patients prefer wearing mandibular (rather than maxillary)
appliances during the day, because they are less visible and patients speak better
with them [4]. Patients should use the appliance as a habit-breaking appliance, so
whenever their opposing teeth touch the appliance, this should alert them that their
muscles are contracted and work at relaxing their muscles. If after 2 months, patients
want to continue wearing the appliance, they should limit their daytime wear to
3–5 h. Patients should never wear their appliance while eating [7].
Tricyclic antidepressants have been shown to be beneficial for musculoskeletal
pain [15]. Patients generally find 25 mg of desipramine taken in the morning and
afternoon helpful and that it does not cause drowsiness.
Additional therapies that are beneficial for both symptom patterns include medi-
cations, physiotherapy (provided by dentists and/or physical therapists), mastica-
tory and cervical exercises, and therapies to relieve neck pain (Tab. 15.5).
Patients generally find topical and oral NSAIDs beneficial for myalgia. Patients
appear to prefer topical NSAID in the gel rather than the liquid formulation, because
it is easier to apply to the masticatory region. Most patients who experience gastric
upset with oral NSAIDs can tolerate the topical formulations. Oral NSAIDs should
not be taken on a continuous basis long term. A low-dose muscle relaxant may be
taken during the day, if it does not cause drowsiness.
Physiotherapy (i.e., heat, ice, ultrasound, iontophoresis, etc.) can also benefit
both daily patterns. Patients can apply heat, ice, or the combination at home multi-
ple times a day. Patients can be referred to a physical therapist who may use these
or other physiotherapy modalities. Patients generally find masticatory and cervical
exercises beneficial; these may be given by the dentist or physical therapist.
Cervical pain can cause referred pain to the masticatory region; patients tend to
unconsciously clench their teeth in response to cervical pain, and the masticatory
muscles often tighten in response to cervical pain. Studies have shown that patients
with cervical pain do not respond to TMD therapies as well as those without cervi-
cal pain [16]. Hence, patients with cervical pain generally have improvement in
their TMD symptoms from cervical therapies.
15.7.2 Myofascial Pain with Referral
Treatment for temporomandibular muscles that are causing referred pain to distant
locations is the same as the treatment for the diagnosis of myalgia. As the muscle
pain improves, the referred pain pattern will resolve.
15.7.3 Spasm
The most effective treatment for a spasm is to stretch the muscle in spasm. A mas-
ticatory muscle spasm does not immediately release once the muscle has been
stretched, so patients will need to be taught how to stretch the muscle and perform
this stretch numerous times throughout the day. This stretch should be slow, gen-
tle, and held in the restricted range. The stretch should be held for 30–60 s, and
the force applied should be determined by patient tolerance while ensuring the
muscle is not aggravated. A series of six stretches with 5 s breaks can be per-
formed sequentially [2, 7].
The stretch is more beneficial if patients first warm the region. The masticatory
muscles in which a spasm most commonly occurs are the lateral and medial ptery-
goid muscles. Since these muscle are not superficial muscles, it would appear that
superficial heat would not be beneficial, but patients commonly report using a heat-
ing pad 15–20 min prior to stretching is helpful [2, 7].
168 E.F. Wright
An analgesic (e.g., 800 mg ibuprofen, tid) is commonly provided for patients with
a spasm; this appears to enable patients to better tolerate the discomfort and allow
patients to provide a better stretch of the muscle. When the disorder is more severe, a
muscle relaxant (e.g., 5 mg diazepam, one to two tablets hs or bid) is indicated. These
therapies are similarly recommended for spasms of other muscles in the body [2, 7].
Within a day or two, patients should start to show signs of improving. Depending
upon the severity of the spasm and patient compliance, full recovery ranges from
days to many weeks. If a patient does not begin to respond to this therapy after 2 or
3 days, consider referring the patient to an orofacial pain specialist [2, 7].
15.7.4 Myositis
If the myositis is due to an infection, the infection must be treated to resolve the
myositis. If the myositis is due to trauma, treatment involves the patient taking a
nonsteroidal anti-inflammatory drug (NSAID), limiting the use of the masticatory
muscles (e.g., soft diet and avoiding oral habits), and applying ice over the affected
area for the first 24–48 h after the trauma; afterwards apply heat and/or ice as desired
[3]. If there is residual muscle pain after these therapies, treat the muscle as described
under the myalgia diagnosis.
• The goal of treatment is to satisfactorily reduce the patient’s pain and restore
masticatory function. The acute disorders are treated as described above and
ensure this is not a reoccurring problem for these patients.
• For patients with chronic disorders, the most prominent contributing factors for
the temporomandibular muscle disorder must be identified. These may entail the
patient’s habits, harmful activities, non-masticatory pains, and psychosocial con-
tributors [4, 7].
• Through the patient’s history, symptomatology, and clinical evaluation, the practi-
tioner can determine the patient’s temporomandibular muscle disorder (Tab. 15.1).
• These contributing factors need to be adequately reduced with a treatment strat-
egy that will be individualized for each patient. Many of these therapies can be
provided concurrently, so complex patients are generally best treated with a team
of providers (e.g., dentist, physical therapist, and psychologist) simultaneously
reducing the various contributing factors within their realm of practice [4].
• TMD self-management therapies (Tab. 15.2) are generally one of the first thera-
pies provided for all of these disorders.
• Myalgia is unquestionably the most common cause for temporomandibular mus-
cle disorders. Numerous therapies are used to treat this disorder, but the most
cost-effective long-term management is determined through identifying and
reducing the patient’s contributing factors.
• Myofascial pain with referral is confusing for both practitioners and patients,
because the pain’s source is at a different location than where the patient per-
ceives it. Practitioners must first rule out pathology at the location it is perceived
and then reproduce the pain by firm palpation of tender regions within the mus-
cle causing this pain. This disorder is a subcategory of myalgia; the muscle is
treated as described for myalgia, and as the myalgia disorder improves, the
referred pain stops.
• Spasm is best treated by patients gently stretching this muscle into its restricted
range numerous times throughout the day. Adjunction therapies of applying heat
prior to the stretches, and taking an analgesic and possibly a muscle relaxant,
should speed recovery. It generally takes days to many weeks for the patient to
obtain full recovery.
• Myositis may be due to an infection or trauma to the muscle. If it is due to an
infection, the infection must be treated to resolve the myositis. If it is due to
trauma, treat with NSAID, soft diet, limiting oral habits, and applying ice over
the affected area for the first 24–48 h after the trauma.
References
1. de Leeuw R, Klasser GD, editors. Orofacial pain: guidelines for assessment, diagnosis and
management, vol. 127. 5th ed. Chicago: Quintessence; 2013. p. 146–8.
2. Wright EF. Medial pterygoid trismus (myospasm) following inferior alveolar nerve block:
case report and literature review. Gen Dent. 2011;59(1):64–7.
3. Clark GT. Classification, causation and treatment of masticatory myogenous pain and dysfunc-
tion. Oral Maxillofac Surg Clin North Am. 2008;20(2):145–57. v
4. Fricton J. Myogenous temporomandibular disorders: diagnostic and management consider-
ations. Dent Clin N Am. 2007;51(1):61–83.
5. Magnusson T, Egermarki I, Carlsson GE. A prospective investigation over two decades on
signs and symptoms of temporomandibular disorders and associated variables. A final sum-
mary. Acta Odontol Scand. 2005;63(2):99–109.
6. Wright EF. Otologic symptom improvement through TMD therapy. Quintessence Int. 2007;
38(9):E564–71.
7. Wright EF. Manual of temporomandibular disorders. 3rd ed. Ames: Wiley Blackwell; 2014.
p. 1–2. 31–70, 97–101, 114–6, 125–9
8. Velly AM, Fricton J. The impact of comorbid conditions on treatment of temporomandibular
disorders. J Am Dent Assoc. 2011;142(2):170–2.
9. Carlsson GE, Egermark I, Magnusson T. Predictors of bruxism, other oral parafunctions and
tooth wear over a 20-year follow-up period. J Orofac Pain. 2003;17(1):50–7.
10. Okeson JP. Bell’s oral and facial pain. 7th ed. Chicago: Quintessence; 2014. p. 287.
Disorders (DC/TMD) for clinical and research applications: recommendations of the
International RDC/TMD Consortium Network and Orofacial Pain Special Interest Group.
12. Blanco Aguilera A, Gonzalez Lopez L, Blanco Aguilera E, De la Hoz Aizpurua JL, Rodriguez
Torronteras A, Segura Saint-Gerons R, Blanco HA. Relationship between self-reported sleep
bruxism and pain in patients with temporomandibular disorders. J Oral Rehabil. 2014;41(8):
564–72.
170 E.F. Wright
13. Madani AS, Abdollahian E, Khiavi HA, Radvar M, Foroughipour M, Asadpour H, Hasanzadeh
N. The efficacy of gabapentin versus stabilization splint in management of sleep bruxism.
J Prosthodont. 2013;22(2):126–31.
14. Lindfors E, Nilsson H, Helkimo M, Magnusson T. Treatment of temporomandibular disorders
with a combination of hard acrylic stabilisation appliance and a soft appliance in the opposing
jaw. A retro- and prospective study. Swed Dent J. 2008;32(1):9–16.
15. Haviv Y, Rettman A, Aframian D, Sharav Y, Benoliel R. Myofascial pain: an open study on the
pharmacotherapeutic response to stepped treatment with tricyclic antidepressants and gaba-
pentin. J Oral Facial Pain Headache. 2015;29(2):144–51.
16. Raphael KG, Marbach JJ. Widespread pain and the effectiveness of oral splints in myofascial
face pain. J Am Dent Assoc. 2001;132(3):305–16.
Orofacial Dystonias and Dyskinesias
16
Gary M. Heir and José L. de la Hoz
Clinical Pearls
• A dentist trained in orofacial pain or oral medicine plays a primary role in
the diagnosis and management of orofacial movement disorders. These
conditions have the potential to impair jaw function, affect orofacial
expressions, facial appearance, and aesthetics, and impact on the quality of
life of these patients.
• The aging population is becoming more dentally conscious, reinforcing
the importance of adequate knowledge of these clinical entities by the oro-
facial pain and oral medicine dental provider, as well as the general dentist,
in order to deliver appropriate treatment to these patients.
• There is a striking lack of methodologically sound studies to support the
various therapeutic options. This reinforces the importance of conservative
and noninvasive restorative modalities that assist in the maintenance of an
orofacial functional equilibrium.
G.M. Heir, DMD (*)

Center for Temporomandibular Disorders and Orofacial Pain,
Rutgers School of Dental Medicine, Newark, NJ, USA
e-mail: heirgm@sdm.rutgers.edu
J.L. de la Hoz, MD, DDS, MS
Master Program in Temporomandibular Disorders & Orofacial Pain, School of Medicine,
CEU San Pablo University, Madrid, Spain

DOI 10.1007/978-3-319-51508-3_16
172 G.M. Heir and J.L. de la Hoz
16.1 Introduction
Orofacial dyskinesia and orofacial dystonia (OFD) includes involuntary muscle

contractions causing slow repetitive movements or abnormal postures. Orofacial
dyskinesia is a group of neurological syndromes characterized by excessive, defi-
cient, or aberration of movement of orofacial structures unrelated to muscle weak-
ness or spasticity [1] and includes blepharospasm, uncontrolled mandibular
depression, puckering of the lips, spasm of the platysma muscle, and uncontrolled
movements of the tongue. It is a neurological condition that is seen in older adults,
usually in seventh decade of life [2].
16.1.1 Basic Functional Neuroanatomy Review
The pyramidal system (PS) is a group of motor axons that travel from the precen-
tral gyrus, or primary cerebral motor cortex, where upper motor neurons (UMNs)
are located. Neurons from the precentral gyrus supply axial and limb muscles.
These axons travel through the brain stem to the anterior horn of the medulla
oblongata, through the corticobulbar tract (CBT) or spinal cord corticospinal
tract (CST), where approximately 75–90% of the axons decussate or cross the
midline within the medulla at a point referred to as the decussation of the
pyramids.
The pyramids are the corticospinal tracts as they pass through the medulla. The
fibers that decussate innervate the limbs and travel through the lateral corticospinal
tract (LCST) to the appropriate spinal cord level where they synapse with lower
motor neurons (LMNs) located in the anterior horn of the spinal cord. The remain-
ing axial fibers, approximately 10%, do not decussate at the pyramidal level. They
travel through the anterior corticospinal tract (ACST) and decussate within the spi-
nal cord, also synapsing on anterior horn cells with the lower motor neurons
(LMNs), which then project to the axial and limb muscles. This explains why the
movements of one side of the body are controlled by the opposite side of the brain.
The PS contains only motor axons (Fig. 16.1).
The nuclei of the UMN are located in the precentral gyrus in the frontal lobe of
the cerebral cortex. This area is also referred to as the “motor strip.” UMNs that
control facial and oral movements are near the Sylvian or lateral fissure. These
axons descend and converge in the cerebral peduncle toward the internal capsule of
the midbrain, forming the CBT and CST (Fig. 16.2).
Axons innervating the facial muscles are located medially (in the CBT) and exit
at different levels to synapse with motor neurons located in the motor nuclei of the
cranial nerves. The axons of the UMN synapse with LMN in the anterior horn of the
spinal cord and their axons, which can measure up to 5 feet in length in tall subjects,
exit through the ventral root of the spinal cord, and converge with the dorsal sensory
tracts to form the spinal nerves that supply the skeletal muscles. Injury of the LMN
results in flaccid paralysis.
16 Orofacial Dystonias and Dyskinesias 173
Motor areas
CEREBRAL
CORTEX
Other areas
Internal capsule Pontine reticular

formation (central
MIDBRAIN group of nuclei)
Middle part of Medullary reticular
basis pedunculi PONS formation
Pyramid (gigantocellular nucleus)
Vestibular nuclei
MEDULLA (lateral vestibular nucleus)
Vestibulospinal tract
Decussation of Pontine reticulospinal

the pryamids tract
SPINAL CORD Medullary reticulospinal
tract
Pontine reticulospinal
tract
Lateral
corticospinal
Ventral
tract
corticospinal
tract
Interneurons and To muscles

motor neurons in (Alpha motor neurons
ventral horn supply extrafusal muscle
Note. The pontine and medullary MIDLINE fibres. Gamma motor
reficular formation receive descending neurons supply intrafusal
afferents, not shown here, from motor fibres.)
areas of the cerebra; corted.
Fig. 16.1 Descending pathways involved in motor control [3]
The CBT includes two motor neurons, the UMN in the primary motor cortex
(Brodmann area 4), and the LMN in the motor nuclei of the cranial nerves. The
axons of the CBT UMN follow the same path, as does the CST to the medulla,
where they synapse with the LMNs. The CBT supplies the nuclei of cranial nerves
bilaterally (with contralateral predominance), except for cranial nerves CN-VII and
CN-XII, which are both contralateral and unilateral.
Fig. 16.2 Primary motor Movement of muscles Central sulcus

cortex, central sulcus, and
Sylvian fissure [4] Supplementary Primary motor
motor area cortex
Premotor Parietal lobe

cortex
Perception of
space and
location of limbs
Plans for
movements
Auditory perceptions
and memories
Visual perceptions
Prefrontal and memories
cortex
Sylvian fissure Temporal lobe Occipital lobe
Cranial nerves with exclusive motor function are CN-IV, CN-VI, CN-XI, and
CN-XII. Those exclusively responsible for sensation are CN-I, CN-II, and CN-VIII,
and those with mixed (motor, sensation, and vegetative parasympathetic) function
CN-III, CN-V, CN-VII, CN-IX, and CN-X.
The extrapyramidal system (ES) is a neural network within the central nervous
system (CNS) and is part of the motor system associated with the coordination of
movement. It consists of polysynaptic nerve pathways including the basal nuclei
(BN) and the subcortical nuclei (SN). This system is called “extrapyramidal” to
distinguish it from the tracts of the motor cortex traveling through the pyramids of
the medulla.
The tracts of the ES arise mainly from the reticular formation of the pons and the
medulla; their target neurons in the medulla and spinal cord are related to reflexes,
locomotion, complex movements, and postural control, complementing the PS that
is responsible for voluntary movement. These tracts are, in turn, modulated by vari-
ous areas of the CNS, including the striatum, the basal ganglia, the cerebellum, the
vestibular nuclei, and various sensory areas of the cerebral cortex. All of these regu-
latory components are considered part of the ES, as they modulate motor activity
without directly innervating the motor neurons. Neurotransmitters involved in the
function of the ES are dopamine, serotonin, acetylcholine, and gamma-aminobutyric
acid (GABA).
The basal ganglia (BG) are composed of an accumulation of cell bodies in the
telencephalon near the base of the brain. They connect with the cerebral cortex,
thalamus, and brain stem. They are associated mainly with unconscious voluntary
movements such as those that involve the entire body controlling routine or every-
day tasks. The BG are in the corpus striatum.
Fig. 16.3 Basal ganglia

[5]
Cortex Caudate
nucleus
Putamen Thalamus
Globus
Subthalamic
pallidus
nucleus
Hypothalamus
Substantia
nigra
The basal ganglia are five prominent nuclei: the caudate nucleus, putamen, glo-
bus pallidus, the subthalamic nucleus, and substantia nigra (Fig. 16.3). Functional
impairment of the BG is associated with a lack of coordination of bodily move-
ments and results in the clinical presentation of diseases such as Parkinson’s dis-
ease, ballism, and Huntington’s chorea.
Extrapyramidal system functions include:
1 . Control of muscle tone

2. Control of body posture
3. Harmonization of motor activity
4. Fine-tuning control of voluntary and involuntary movements
According to the anatomical clinical presentation, orofacial dystonias and dyskine-

sias are classified as follows:
• Focal: blepharospasm, torticollis, oromandibular dystonia, spastic dysphonia,

writer’s cramp, occupational cramp
• Segmental: two or more contiguous parts of body, e.g., cranial + brachial, cra-
nial + axial, cranial + cervical (Meige’s syndrome)
• Generalized: involves several regions on both sides of the body, e.g., combina-
tion of leg involvement in addition to other body areas
• Multifocal: involves two or more noncontiguous parts of the body

• Hemidystonia: affects one-half of the body – symptomatic rather than primary
The most common forms of dystonia and dyskinesia include blepharospasm or

twitching around the eye; cervical dystonia or spasmodic torticollis affecting the
neck; segmental cranial dystonia such as Meige’s’syndrome affecting the jaw,
tongue, and eyes; oromandibular dystonia affecting the jaw, tongue, and lips; spas-
modic dysphonia affecting the vocal cords; axial dystonia affecting the trunk; and
dystonia of the arm, e.g., writer’s cramp.
The etiology underlying movement disorders can be genetic, primary/idiopathic, or

secondary/acquired during adulthood (due to functional overuse, medications, den-
tal treatment, etc.); however, the majority are not well understood.
The prevalence of bruxism (sleep and awake) in the adult population is 20%,
with a female predominance [6, 7]. Sleep bruxism (SB) is estimated as present
in approximately 8% of the population, making it the most common of the OFDs
[8]. The prevalence of SB in children is estimated at 14–20%, 13% in young
adults between the age of 18 and 29, 9% in adults aged 30–65 years, and 3% in
persons beyond 65 years [9, 10]. Awake bruxism has a prevalence of 22%,
1–31% [11].
The prevalence of oromandibular dystonias is 3–30/100,000 in the US popula-
tion [12]. It is more common in women between 30 and 70 years [13].
Primary idiopathic dyskinesia typically affects the elderly population. The prev-
alence ranges between 1% and 38%, being two to three times more common in
women, though this difference may be partly due to methodological biases of epi-
demiological studies [14].
The general prevalence of secondary dyskinesias (also named tardive dyskine-
sia or TD) in patients treated with neuroleptic medications is approximately 20%,
with a variable incidence depending on age and gender. It is more frequent in the
elderly and females [15]. No epidemiological data exist regarding the prevalence
of TD in various psychiatric disorders nor the duration of exposure or dose-related
risk for its occurrence, indicating an individual susceptibility trait. However, the
prevalence of tardive dyskinesia seems to be dependent on the type of antipsy-
chotic drugs used.
The exact pathophysiological mechanisms underlying movement disorders are not

completely understood. Normally, the prefrontal cortex gathers information to plan
and execute movement by projecting signals to the premotor cortex and
supplementary motor area, and then to the primary motor cortex. This, in turn sig-
nals the appropriate area of the spinal cord for movement.
The basal ganglia regulate the initiation, grading, and control of the ampli-
tude and direction of movement. At the same time, some movements are
facilitated, while others are suppressed, controlling fine, coordinated move-
ments. Movement disorders may arise from biochemical or structural abnor-
malities in the BG “braking” system which prevents the target structures from
generating unwanted motor activity. Many available muscles may be acti-
vated at any given time. For example, when altered as in disorders such as
Huntington’s disease or Wilson disease, unwanted movements such as invol-
untary jerking movements of an arm or leg or spasmodic movement of facial
muscles occur.
There are several hypotheses for dysfunction of this system that include basal
ganglia dysfunction and hyperexcitability of interneurons involved in motor signal-
ing [16]; reduced inhibition of spinal cord and brain stem signals coming from
supraspinal input; and dysfunction of neurochemical systems involving dopamine,
serotonin, and noradrenaline [17].
Other risk factors for developing movement disorders include injury at birth,
e.g., lack of oxygen, infection, reactions to medications, heavy metal poisoning,
carbon monoxide poisoning, trauma, stroke, and inherited abnormalities of the
basal ganglia.
Depending on the location of the pathology, movement disorders include:
1. Lesion of the PS:

(a) Weakness or paralysis of the muscles responsible for the movements
2. Lesion of the ES:
(a) Altered muscle tone, posture, and coordination of movements
Orofacial movement disorders can be classified as follows:
1. Deficit of movement:
(a) Akinesia (lack of movement)
(b) Hypokinesia (decreased range of motion)
(c) Bradykinesia (slowness of movement)
2. Excess of movement (hyperkinesias or dyskinesias)
(a) With jerky movements:
(i) Myoclonus/tics
(ii) Chorea (including ballism)
(b) No jerky movements:
(i) Dystonia (including athetosis
(ii) Tremor
Hypokinesia is generally referred to as Parkinsonism and includes:
1 . Idiopathic Parkinsonism or Parkinson’s disease

2. Secondary Parkinsonism to medications, toxins, drugs, infections
3. Atypical Parkinsonism: syndromes related to Parkinson’s disease associated with
other degenerative neurological disorders – multiple systemic atrophy, progressive
supranuclear palsy, corticobasal ganglionic degeneration, Lewy’s body disease
Hyperkinesias/dyskinesias include [18]:
1. With jerky movements:

(a) Myoclonus/tics
(b) Chorea (including ballism)
2. No jerky movements:
(a) Dystonia (including athetosis)
(b) Tremor
3. Additional classifications include:
(a) Fast: myoclonus/tics, chorea, ballism
(b) Slow: dystonia, athetosis
(c) Rhythmic: tremor
16.5.1 Orofacial Dyskinesias
Orofacial dyskinesias are caused by the functional impairment of cranial nerves V,

VII, and XII affecting the masticatory muscles, muscles of facial expression, and
the lingual musculature [19]. These result from anomalies in the basal ganglia and/
or in their interaction with other areas of the brain and can be divided into dystonias
and dyskinesias. Dystonias are brief and recurrent sustained muscle contractions
that cause abnormal movements and postures. Dyskinesias are involuntary, repeti-
tive, and uncoordinated muscle movements.
Orofacial dyskinesias may be:
• Primary, idiopathic, or essential

• Secondary or tardive
• “Dental” (to be discussed later in this chapter)
• Orofacial dyskinesias are as follows [20]:
–– Bruxism
–– Oromandibular dystonia
–– Orofacial dyskinesia
• Drug-induced dystonic-type extrapyramidal reactions (DERs)
16.5.2 Bruxism
Bruxism is a repetitive jaw muscle activity characterized by clenching or grinding

of the teeth and/or by bracing or thrusting of the mandible. Bruxism has two distinct
circadian manifestations: it can occur during sleep (referred to as sleep bruxism) or
during wakefulness (referred to as awake bruxism) [21]. For more information on

awake bruxism, please review Chap. 12.
Pathophysiology is multifactorial with elements such as genetic predisposition,
sleep structure (microarousals), environment, emotional distress, anxiety, and other
psychological factors. CNS catecholaminergic imbalance, autonomic nervous sys-
tem dysfunction, some recreational drugs (ecstasy, alcohol, caffeine, tobacco), and
medications (e.g., selective serotonin reuptake inhibitors, and benzodiazepines,
dopaminergic drugs) play a significant role [22].
Currently, the etiology of sleep bruxism is considered as a central and autonomic
nervous system etiology beginning as oromandibular activity during sleep. Motor
activities may increase during sleep and induce rhythmic masticatory muscle activity
(RMMA). This represents jaw movements secondary to this muscle activity seen as
bruxism [23]. It is further suggested that bruxism secondary to RMMA may be trig-
gered by brief brain stem arousal in the reticular ascending system contributing to an
increase in activity of autonomic-cardiac and motor modulatory networks [24].
Clinically, bruxism may result in oral manifestations including abnormal tooth
wear, failure of dental restorations or fracturing of teeth, indentations of the lateral
borders of the tongue, gingival recessions, linea alba along the biting plane or max-
illary/mandibular tori, muscular or articular pain (arthrogenous temporomandibular
disorder [25]), and headaches among other symptoms. Contrary to general belief in
the dental and medical professions, most chronic bruxers do not present with pain-
ful or functional symptomatology related to jaw function [26].
Presently, there is no treatment that effectively or permanently eliminates brux-
ism [27]. Consequently, the therapeutic management aims to prevent and treat the
eventual detrimental effects that bruxism may have on the masticatory system.
Conservative multimodal approach by means of muscle relaxants, oral appliances,
physical therapy, and psychoemotional counseling is enough, in most cases, to
obtain this goal for daytime bruxism [27]. Nocturnal bruxism is considered a move-
ment disorder associated with sleep [28–30]. For those cases in which the conserva-
tive approach does not adequately control the bruxing habit, the use of botulinum
toxin has offered positive results [31].
16.5.3 Oromandibular Dystonia
Oromandibular dystonia (OMD) is a focal dystonia in which patients present with

intermittent, short-lasting, sustained, and recurring muscle contractions of the mas-
ticatory, facial, and/or lingual musculature [32]. There may be opening, closing, or
deflected movements, usually bilateral, due to a central origin [33]. In some
instances, it can significantly compromise the quality of life of the patient affecting
speech, mastication, swallowing, and social interaction [34].
Pathophysiology is due to [17]:
• Basal ganglia dysfunction

• Hyperexcitability of interneurons
• Failure (inhibition) of spinal and medullar neuromodulation
• Dopaminergic, serotonergic, and/or adrenergic systems dysfunction
There are of three types of OMD: primary, idiopathic, or essential (±63%).

Secondary OMD include trauma, tumor, brain stem injury, systemic conditions
(MS, Parkinson, cerebral vascular stroke), and due to medications/drugs (DER).
OMD may occur concomitant to placement of “dental or prosthetics” (to be dis-
cussed later in this chapter), in the presence of stress, exposure to glaring lights,
driving, reading, talking, praying, fatigue, and chewing, which may act as triggering
or aggravating factors [33]. Conversely, OMD may diminish when relaxing, talking,
singing, humming, lip biting, tongue posturing, swallowing, chewing gum, and in
some instances with the intake of alcohol [35]. In addition, the tactile stimulation of
the affected area (“sensory trick” or “geste antagoniste”) [36] or the use of certain
types of sensory feedback intraoral devices [37] may diminish or temporarily elimi-
nate the dystonic movement. This is more frequent in the OMD.
If OMD presents with blepharospasm (focal dystonia of the orbicularis oculi
muscles), it is called Meige’s or Brueghel’s syndrome [33].
16.5.4 Orofacial Dyskinesia
Orofacial dyskinesia (OD) is defined as involuntary, repetitive, stereotypical move-

ment of the face, tongue, and jaw that may be occasionally painful [38]. It may
present as one of these three types:
1 . Primary or idiopathic
2. Secondary (a.k.a. tardive dyskinesia)
3. “Dental or prosthetic” (to be discussed later in this chapter)
16.5.4.1 Primary or Idiopathic Dyskinesia

Primary or idiopathic dyskinesia is frequently comorbid, but not secondary to
schizophrenia, Alzheimer’s disease, dementia, autism, mental retardation, and Rett
syndrome. It has been suggested that in these cases, the use of medications to treat
these conditions may unmask dysfunctional subcortical circuits and trigger a dyski-
nesia in a predisposed patient [39]. The clinical presentation is usually milder than
that of tardive dyskinesia.
16.5.4.2 Secondary or Tardive Dyskinesia (TD)

The clinical presentation consists of rapid, repetitive, nonrandom, stereotypic move-
ments involving the tongue, lips, and jaw areas secondary to exposure to an offend-
ing drug, typically conventional antipsychotic drugs, such as chlorpromazine,
haloperidol, and perphenazine [40]. Trunk and muscles of the extremities are also
occasionally involved.
TD is a secondary condition that arises in some instances due to the use of certain
drugs, mainly neuroleptic medications [40] and occasionally other dopamine
receptor-blocking agents, such as atypical antipsychotic drugs, antiemetics, tricy-
clic antidepressants, and selective serotonin reuptake inhibitors. The clinical pre-
sentation consists of rapid, repetitive, nonrandom, stereotypic movements involving
the tongue, lips, and jaw areas. They may present in combination with tongue
twisting and protrusion, lip smacking and puckering, and chewing movements.
Occasionally trunk and extremities are involved. Several activities and other factors
may temporarily interrupt or increase the intensity of the dyskinesia.
TD seems to be due to hypersensitivity of basal dopaminergic receptors by chemical
denervation due to chronic blockade with these medications. However, this does not
explain why TD only appears in ±20% of patients treated pharmacologically. Other
pathophysiological hypotheses have been formulated such as an underlying polymor-
phic genetic susceptibility due to the association between serine and glycine in exon 1
of the gene DRD3 [41]. Other possible anomalies are the presence of alterations in
GABAergic pathways, adrenergic and cholinergic production, and O2 radicals [42].
The diagnosis of TD requires a minimum of 3 months of treatment and persis-
tence of symptoms beyond 3 months after discontinuation of treatment.
Drug-induced extrapyramidal reactions (DERs) are a group of oromotor hyper-
activity disorders triggered by the use of certain medications and illegal or stimulant
drugs (Table 16.1). In Table 16.2, a list of medications/drugs known to induce drug-
induced extrapyramidal reactions (DERs) and subsequent orofacial movement dis-
orders can be viewed.
Table 16.1 Clinical forms Dystonia (involuntary, tonic contractions of skeletal muscles)
of drug-induced extrapyrami- Akathisia (subjective experience of motor restlessness)
dal reactions (DERs) Parkinsonism (tremor, rigidity, and akinesia or bradykinesia)
Table 16.2 Medications and drugs related to drug-induced extrapyramidal reactions (DERs)
Common medications prescribed by health-care professionalsa
Fluoxetine
Fluvoxamine
Paroxetine
Sertraline
Citalopram
Escitalopram
Uncommon stimulant drugs prescribed by health-care professionals or illegalb
Methylphenidate
Phentermine
Pemoline
Dextroamphetamine
Amphetamines
Diethylpropion
Illegal stimulant drugsc
Methamphetamine
Cocaine
3,4-Methylenedioxymethamphetamine (ecstasy)
Notes:
a
Prescribed for the treatment of depression and anxiety. Rather than a clenching or grinding brux-
ing type of masticatory musculature hyperactivity, patients complain of muscle pain, facial tight-
ness, and fatigue due to sustained isometric muscle contraction
b
Used for the treatment of obesity, attention deficit hyperactivity disorder, and narcolepsy
c
May cause tooth clenching and grinding, tics, and dystonic reactions
16.5.4.3 “Dental or Prosthetic” Dyskinesias

There are isolated reports in the literature that implicate dental treatment as a factor
in the onset of orofacial dyskinesia [43, 44]. It has been suggested that wearing ill-
fitting prostheses poses a higher risk factor for oral stereotypes than not wearing
prostheses [45]. Several factors, such as ill-fitting and unstable prostheses, oral dis-
comfort, and lack of sensory contacts, have been proposed to explain the patho-
physiology of oral dyskinesia in the so-called prosthetic stereotypes, but the exact
mechanism remains unclear [46].
Providing a correct differential diagnosis of OFD is of upmost importance in order

to establish the appropriate therapeutic protocol in which the OFP dentist must be
part of the interdisciplinary team. A comprehensive neurological examination
including MRI and MR angiography is necessary to rule out the possibility that the
motor dysfunction may be due to a central degenerative, demyelinating, space-
occupying, or sclerotic lesion of the nervous system. OFDs may be primary or
essential, secondary to the use of certain medications (as SSRIs in bruxism or neu-
roleptics as in tardive dyskinesias) or illegal recreational drugs (amphetamine,
cocaine, ecstasy), or comorbid with some hereditary or neurological degenerative
disease (Parkinsonism, choreas, tremors, tics, orofacial dyskinesias) or psychiatric
diseases [47].
Characteristic clinical features including amelioration by action, augmentation
by distraction, partial volitional suppressibility, and lack of subjective distress help
differentiate TD from other movement disorders such as resting tremor, Huntington’s
disease, spontaneous dyskinesias, and abnormal movements accompanying psychi-
atric illnesses [48].
The dentist is responsible for the examination and diagnosis of possible local
pathological causes of the masticatory system (masticatory, perioral/facial, or
tongue muscles).
Electromyographic assessment may be indicated to identify specifically which
muscles are involved and to assess the patient for a motor or sensory nerve con-
duction deficit, a peripheral-origin myopathic disease, or motor neuron
abnormality.
In severe cases of bruxism, including some forms of myoclonic-type bruxism, it
will be necessary to conduct a nocturnal polysomnogram [20].
Identification and withdrawal from medications with the propensity toward induc-
ing dyskinesia should be the first objective of treatment. Adjustment of a pharmaco-
logical regimen, rather than adding another medication, may be effective, however,
not in all cases.
Where dyskinesia or dystonia may be due to neurotransmitter imbalance, certain

medications may help to correct these imbalances [49]. They include the following:
Anticholinergics, which are typically the most effective. However, side effects
including dry mouth, blurred vision, constipation, and urinary retention must be
considered. Narrow-angle glaucoma is a contradiction.
Trihexyphenidyl, typically, the first choice, is a muscarinic acetylcholine receptor
antagonist. It is useful for generalized and segmental dystonia [50]. Side effects
are dose related and include drowsiness, confusion, difficulty with memory, and
hallucination. One of the more prominent side effects is dry mouth. It may also
cause nausea. Dental hygiene in medication-induced hyposalivation is important
to prevent caries. Other side effects include blurred vision, dizziness, headache,
photophobia, lightheadedness, constipation, loss of appetite, trembling of the
hands, and vomiting.
Baclofen targets presynaptic GABA receptors. Acting as a GABA agonist, it is
effective in treating spasticity. Baclofen may be helpful for oromandibular dys-
tonia. Side effects include dizziness, weakness, drowsiness, tiredness, headache,
difficulty with sleep, nausea, constipation, and increased urination. Care must be
taken when administering baclofen to diabetics as the blood glucose levels may
increase. Discontinuation of baclofen must be gradual.
Benzodiazepines, of which clonazepam is the most commonly prescribed, may be
effective for a small percentage of patients [51]. They may be useful for treat-
ment of head tremor [52, 53], cervical dystonia, and blepharospasm [54]. These
medications are useful as short-term muscle relaxants for reduction of skeletal
muscle tone, and may have some utility for the relief of painful muscle contrac-
tions or spasms. The use of benzodiazepines in the elderly should be avoided due
to the side effect of dizziness and weakness that may result in falling. Other side
effects include sedation, cognitive impairment, and disturbed sleep patterns.
Rapid withdrawal may result in seizures.
Dopaminergic medications are inconsistent in the treatment of dystonias supporting
the etiological heterogeneity of dystonia and dyskinesia [55]. Treatment with tet-
rabenazine and reserpine, presynaptic dopamine depleters, has met with some
success. Trials of dopamine receptor antagonists have also been met with mixed
results [56]. Levodopa is rarely helpful in patients with idiopathic or other types
of dystonia. Numerous side effects have been reported with the use of dopaminer-
gic medications including headache, anxiety, nausea, vomiting, and chills. Less
frequent side effects reported include chest pain, palpitations, and confusion.
Botulinum toxin injections, directly in the muscles affected by dystonia, can result
in their weakening. This may improve symptoms for 3–4 months. This can be
effective treatment for focal dystonias such as oromandibular dystonia, blepha-
rospasm, dysphonia, and cervical dystonia.
Surgery to ablate the nerves leading to muscles affected by dystonia or removing

the muscles altogether may help reduce dystonic muscle contractions. This tech-
nique of selective denervation is mostly indicated for cervical dystonia [57]. Some
Table 16.3 Other potentially Blepharospasm

useful pharmacologic and Clonazepam, lorazepam
nonpharmacological therapies Botulinum toxin
for orofacial dystonias and
Trihexyphenidyl
dyskinesias
Orbicularis oculi myectomy
Oromandibular dystonia
Baclofen
Trihexyphenidyl
Botulinum toxin
Jaw closure dystonia
Masseter muscle
Jaw opening dystonia
Submental muscle or lateral pterygoid muscle
Spasmodic dysphonia
Botulinum toxin
Cervical
Trihexyphenidyl
Diazepam, lorazepam, clonazepam
Botulinum toxin
Tetrabenazine
Carbamazepine
Baclofen
Task-specific dystonia (writer’s cramp)
Benztropine, trihexyphenidyl
Botulinum toxin
Occupational therapy
success has been reported with deep brain stimulation to reduce symptoms of dys-
tonia [58]. Nonpharmacological or surgical treatment includes physical and sup-
portive therapy, substitute for a “sensory trick,” muscle relaxation techniques, and
sensory feedback therapy.
Other treatment options are displayed in Table 16.3.
The dental management of orofacial movement disorders is necessary when daily

jaw functions are impaired. The restorative dentist plays a primary role in the man-
agement of the dental implications of OFD [59]. Unfortunately, there is a significant
lack of evidence-based scientific literature to support the possible associations and
efficacy of therapeutic dental modalities for these clinical entities. Most publica-
tions are dated and empirically based clinical reports [60–62]. It must be empha-
sized that dental treatment can only assist in the improvement of oral health and
masticatory function and accordingly contribute to the maintenance of an adequate
nutritional status of the OFP patient but will not provide a definitive solution for
these complex multifactorial pathologies.
Several therapeutic modalities are available as adjuvants in the control of the

orodental consequences of OFD, such as the prudent and judicious use of correctly
adjusted oral appliances to distribute and optimize the occlusal load and prevent the
damage to dental structures. In some instances, these appliances may also play the
role of a “sensory trick,” temporarily alleviating the intensity of the dyskinetic
movement.
Fixed, either conventional or implant-supported, prosthodontic restorations are
preferable over removable options to facilitate retention and prevent orodental inju-
ries due to uncontrolled movements. These restorations must be carefully planned,
designed, and adjusted using the least invasive restorative procedures to facilitate
their integration in the already hypersensitive masticatory system of the patient in
order to assist in the maintenance of the functional equilibrium and minimize any
peripheral input that could act as trigger of the OFD.
A comprehensive clinical examination including mounted study casts, interoc-
clusal records, correct vertical dimension, static and dynamic intermaxillary rela-
tions, and restorative material selection is of upmost importance.
Occasionally, dental treatment must be provided under conscious sedation or
general anesthesia.
16.9 Conclusion
The primary responsibility of the dental practitioner confronted by a patient with

abnormal facial or jaw movements is first to arrive at a differential diagnosis. This
may be a difficult task, but depends on a detailed history including a review of sys-
tems, physical and psychological disorders, and knowledge of past or current medi-
cations. Once recognized as a movement disorder rather than parafunction, the
dental practitioner, working with the appropriate health-care providers, plays the
important role of maintaining health of the dentition and all intraoral structures to
maintain optimal function regarding facial expressions and appearance, and to facil-
itate adequate nutrition. Care must be taken to provide conservative, or the least
invasive treatment and maintenance of the oral cavity, as in many cases the etiology
of movement disorders affecting masticatory musculature is unclear.
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mphetamine (ecstasy) abuse. Clin Toxicol. 2010;48(8):863–4. 2p. 2.
Occlusal Dysesthesia and Dysfunction
17
Somsak Mitrirattanakul, Tan Hee Hon,
and João N.A.R. Ferreira
Pearls of Wisdom
• The majority of the clinical research studies had agreed on one point: any
dental procedure (occlusal adjustment, restorative, prosthetic, or orthodon-
tic approaches) that aims to achieve equilibrated occlusal contacts between
the maxillary and mandibular teeth (in maximum intercuspation) must be
avoided in patients with occlusal dysesthesia (OD).
• Therefore, any dental procedure that interferes with the occlusion of OD
patients usually fails to improve the symptoms but could increase the
patient’s somatosensorial focus on his or her bite.
17.1 Introduction
Occlusal dysesthesia (OD) is characterized as persistent (more than 6 months)

uncomfortable or distressing bite sensations which are not affected by any physical
alteration related to the occlusion, pulp, periapical tissue, muscles of mastication, or
the temporomandibular joint (TMJ). This condition can cause significant functional
impairment [4–6]. Other terms for this condition are phantom bite, occlusal neuro-
sis, occlusal mania, positive occlusal awareness, and occlusal hyperawareness.
S. Mitrirattanakul, DDS, PhD (*)

Department of Masticatory Science, Faculty of Dentistry, Mahidol University,
Bangkok, Thailand
e-mail: sammu99@gmail.com
T.H. Hon, BDS, MDS (Prostho)
Endodontics, Operative Dentistry & Prosthodontics, Faculty of Dentistry, National University
of Singapore, Singapore, Singapore
J.N.A.R. Ferreira, DDS, MS, PhD, Dip. ABOP
Oral & Maxillofacial Surgery, Faculty of Dentistry, National University of Singapore,

DOI 10.1007/978-3-319-51508-3_17
190 S. Mitrirattanakul et al.
Patients with occlusal dysesthesia may present the following clinical scenarios:
• Sensorial complaint that “bite is off.”

• History of unsuccessful dental treatments.
• Unable to define a comfortable bite position.
• Symptoms are exacerbated by dental treatments that focus only on attempting to
restore the “ideal” occlusion.
17.3.1 Epidemiology
OD is generally considered a rare condition [7], although no precise data on its

prevalence and incidence in the population have ever been reported [8]. However, in
a survey of patients with temporomandibular disorders (TMD), over 30% reported
some bite discomfort, and about 10% reported uncomfortable bite almost all of the
time [9, 10]. It seems to be differently distributed between the genders with higher
female prevalence [1, 3, 11–14], similarly to the higher female prevalence of TMD
that sometimes is comorbid with the disease [2, 8, 15, 16]. However, such female
preponderance is not reported in all the studies [8, 9]. The age of the patients can
vary widely from 20 to 80 years with a mean age of 40–50 years [1, 8, 11, 14]. First,
onset of the symptoms occurs at the mean age of 45 years, with mean time of symp-
toms’ duration of 6 years [1]. In a survey by Watanabe et al. [14], among 130 patients
over 70% reported that symptoms developed after a dental treatment.
17.3.2 Etiology
There is no consensus on the etiology and characteristics of OD. Current literature

proposed that OD etiologies are related to both neurophysiology of the masticatory
proprioceptive system and psychological disorders manifested in the orofacial
region.
There are three hypotheses which attempt to explain this unusual condition:
I. Psychiatric disorders: various studies based on psychological consultations

have associated OD symptoms with somatoform disorders. The symptoms
were characterized by obsessive focus on the tooth morphology, dental
17 Occlusal Dysesthesia and Dysfunction 191
occlusion, as well as misinterpretation and exacerbation of normal occlusal

contact patterns. The patients also presented detailed information of the psy-
chological interaction of heightened threat, health anxiety, and cognition. In
addition, the degree of the perceived physical distress could be altered by
mood changes.
II. Phantom phenomenon and neuroplasticity: this hypothesis is based on the the-
ory that the brain encompasses the self-knowledge of the whole body as an
entity. This could be represented as a neuronal network. This brain network
could normally be activated and modulated by external stimuli, but it can also
be triggered without any peripheral input. It has been assumed that “the knowl-
edge of dental anatomical details comprising the individual’s dental occlusion
exists in the brain as a coherent unit or “occlusal neurosignature.” For vulner-
able patients, tooth contact pattern alterations are caused by tooth movement,
extraction, or restorative procedures which could be compared as a body part
amputation, which in turn could lead to an ambiguous interpretation between
the memory of the “loss of bite” and the actual bite within the occlusal neuro-
signature. The patient could not therefore accept the altered occlusal contact
pattern as his own original bite leading to an endless exploration for the “cor-
rect bite.”
III. Altered oral proprioceptive inputs and transmission: this etiologic concept pro-
posed that the main cause of OD is due to a proprioceptive dysfunction, that is,
a false peripheral feedback to the central nervous system. The main etiological
factor could be caused by the “sensitization” of the periodontal mechanorecep-
tors of the involved teeth, which could produce an altered peripheral input or
hyperawareness signal from the teeth.
There are several clinical red flags for OD such as complaint of overly disabling bite
discomfort, demonstrating substantial obsessive somatic focus and excess emo-
tional distress, exhibiting detailed histories of their problem and of prior treatment
failures, expressing anger at their previous dentists and dental procedures, and
showing high expectations of the treatment outcome.
Suggested Criteria for the Diagnosis of OD [11]
1 . Complaint of uncomfortable bite sensation

2. Significant associated emotional distress
3. The symptoms lasting for more than 6 months
4. History of various bite-altering dental procedure failures
5. Absence of dental occlusal discrepancies or disproportional to the complaint
6. Not attributed to another disorder (dental pathology, muscle, temporomandibular
joint, or neurologic disorder)
192 S. Mitrirattanakul et al.
Since OD is not an exclusively physical problem, and the condition is significantly

involving some level of psychological disorders, behavioral approach, e.g., patient’s
education, is the most important treatment tool. In addition, cognitive-behavioral
therapy (CBT) had been proposed as a key concept for the management of OD. This
treatment concept will focus on four specific areas of intervention: cognition, atten-
tion, context, and mood.
The aims of CBT for somatoform disorder are to:
• Reduce physiological arousal and reactivity through relaxation and mindfulness

techniques
• Improve activity regulation through increasing exercise and meaningful
activities
• Increase awareness of emotions and learn to regulate their emotion and develop
tolerance of distress
• Address comorbid mood disturbance
• Modify dysfunctional beliefs through cognitive restructuring
In order to improve the symptoms and enhance the quality of the sufferers’ lives,
OD patients need to understand that there is a need to take control of their symptoms
via the application of self-management physical medicine and cognitive-behavioral
treatment modalities. However, not all patients are going to respond to therapy. This
would be very much dependent on the severity of the disorder and its comorbid
physical and psychological conditions.
Based on the biopsychosocial approach model, the following specific treatment

strategies for OD are proposed:
1 . Do not try to convince the patient that nothing is wrong with their bite.
2. The treatment needs to be structured on time-limited visits with an emphasis on
behavior change through self-management modalities. The patient needs to
understand that symptom reduction will occur only through their actions and
efforts.
3. The CBT and relaxation may need to be introduced before the physical medicine
modalities. It may be important to treat the comorbid psychological concerns
first before beginning the physical medicine approach.
4. The dentist should not attempt to treat the bite complaint with occlusal adjust-
ments before working with the tight and/or painful muscles. Adjusting the bite
17 Occlusal Dysesthesia and Dysfunction 193
will feed the somatization and shift the patient’s attention to their bite and occlu-
sal splint or device.
5. The important role of the dentist in the treatment process is to help the patient to
dissociate the bite from their obsessive focus by assisting them to alternatively
focus on something that is beneficial for them, such as doing jaw stretching
throughout the day and maintaining a jaw posture where the teeth are not touch-
ing. Dentist should take the opportunity to educate the patient to use their symp-
tom as a reminder to employ the adaptive coping behaviors.
6. The patient is instructed neither to check their bite nor to allow their teeth to
come together. This can be achieved by using mnemonics like “lips together,
teeth apart” or “jaw dropped, teeth apart” or “tongue up, teeth apart.”
7. The patient should be given positive feedback for their attempts to comply with
the recommendations and encouraged to persist if they fall back.
References
1. Baba K, Aridome K, Haketa T, Kino K, Ohyama T. Sensory perceptive and discrimina-
tive abilities of patients with occlusal dysesthesia. Nihon Hotetsu Shika Gakkai Zasshi.
2005;49:599–607.
2. Clark G, Simmons M. Occlusal dysesthesia and temporomandibular disorders: is there a link?
Alpha Omegan. 2003;96:33–9.
3. Clark GT, Minakuchi H, Lotaif AC. Orofacial pain and sensory disorders in the elderly. Dent
Clin N Am. 2005;49:343–62.
4. Hara ES, Matsuka Y, Minakuchi H, Clark GT, Kuboki T. Occlusal dysesthesia: a qualita-
tive systematic review of the epidemiology, aetiology and management. J Oral Rehabil.
2012;39:630–8.
5. Jagger RG, Korszun A. Phantom bite revisited. Br Dent J. 2004;197:241–3.
6. Littler B. Phantom bite revisited. Br Dent J. 2005;198:149.
7. Marbach JJ, Varoscak JR, Blank RT, Lund P. “Phantom bite”: classification and treatment.
J Prosthet Dent. 1983;49:556–9.
8. Marbach JJ. Phantom bite syndrome. Am J Psychiatry. 1978;135:476–9.
9. Marbach JJ. Phantom bite. Am J Orthod. 1976;70:190–9.
10. Marbach JJ. Psychosocial factors for failure to adapt to dental prostheses. Dent Clin North Am.
1985;29:215–33.
11. Melis M, Zawawi KH. Occlusal dysesthesia: a topical narrative review. J Oral Rehabil.
2015;42:779–85.
12. Mew J. Phantom bite. Br Dent J. 2004;197:660.
13. Reeves JL, Merrill RL. Diagnostic and treatment challenges in occlusal dysesthesia. J Calif
Dent Assoc. 2007;35:198–207.
14. Tinastepe N, Kucuk BB, Oral K. Phantom bite: a case report and literature review. Cranio.
2015;33:228–31.
15. Toyofuku A, Kikuta T. Treatment of phantom bite syndrome with milnacipran – a case series.
Neuropsychiatr Dis Treat. 2006;2:387–90.
16. Watanabe M, Umezaki Y, Suzuki S, et al. Psychiatric comorbidities and psychopharmacologi-
cal outcomes of phantom bite syndrome. J Psychosom Res. 2015;78:255–9.
Part VII
Orofacial Pain Disorders
Non-odontogenic “Tooth” Pain
18
Flavia P. Kapos and Donald R. Nixdorf
Pearls of Wisdom
• Non-odontogenic “tooth” pain characteristics are the key to identifying the
underlying disorder: a detailed pain history will guide most of the diagnos-
tic process.
• Pain can be referred from local and distant structures, including musculo-
skeletal, neuropathic, and neurovascular sources.
• Response to provocation tests and administration of local anesthetic may
help to rule out or confirm the origin of the pain, as well as determine
therapeutic approaches.
• Treatment options vary widely by diagnosis and are directed at the mecha-
nism of the source of pain.
• Missed non-odontogenic “tooth” pain diagnoses may result in unnecessary
dental procedures, as well as continued symptomatology.
F.P. Kapos, DDS, MS (*)

Division of TMD & Orofacial Pain, Department of Diagnostic and Biological Sciences,
School of Dentistry, University of Minnesota, Minneapolis, MN, USA
Department of Oral Health Sciences, School of Dentistry, University of Washington,
Seattle, WA, USA
Department of Epidemiology, School of Public Health, University of Washington,
Seattle, WA, USA
e-mail: kapos@uw.edu
D.R. Nixdorf, DDS, MS
Division of TMD & Orofacial Pain, Department of Diagnostic and Biological Sciences,
School of Dentistry, University of Minnesota, Minneapolis, MN, USA
Department of Neurology, Medical School, University of Minnesota, Minneapolis, MN, USA
HealthPartners Institute for Education and Research, Bloomington, MN, USA
DOI 10.1007/978-3-319-51508-3_18
198 F.P. Kapos and D.R. Nixdorf
Pain presenting in the orofacial region, including the teeth, can arise from various
local and distant structures. While the most common causes of tooth pain are odon-
togenic, most other pain-producing orofacial disorders covered elsewhere in this
book may also mimic tooth pain. Especially when dental etiologic factors are not
evident, or pain does not respond to standard treatment, non-odontogenic causes
should be considered in the differential diagnosis.
Non-odontogenic “tooth” pain is referred to as heterotopic pain, meaning that it
is felt in a different anatomical location than its actual source. Sources of non-
odontogenic “toothache” could be of any one or more of the five following types:
• Musculoskeletal
• Neuropathic
• Neurovascular/headache disorders
• Referred pain from regional or distant pathology
Each of these broad pain categories is generally associated with certain pain
characteristics such as onset, timing, duration, quality, intensity, aggravating/allevi-
ating factors, and associated features. Therefore, a thorough pain history may reveal
clues about the true origin of the symptoms to the knowledgeable clinician [1].
Common causes of non-odontogenic “tooth” pain include the following disorders:
• Myofascial pain with referral (temporomandibular disorders – TMD)

• Persistent dentoalveolar pain disorder (PDAP)
• Trigeminal neuralgia (TN)
• Headache disorders, such as migraine headaches and trigeminal autonomic
cephalalgias
Other regional or distant pathology that may also produce tooth pain-like
symptoms:
• Cardiac pain/angina pectoris

• Sinus/paranasal mucosa pain
• Neoplasias of the head and neck
In such instances, for pain relief to occur, treatment must be directed at the
underlying pain-producing disorder and its mechanisms and not at the tooth site
where the pain is perceived to be [2]. This chapter will focus on the keys for the
identification of the most probable causes of non-odontogenic “tooth” pains. Please
refer to specific chapters in this publication for a more in-depth discussion on diag-
nosis and management strategies for each of these disorders.
18 Non-odontogenic “Tooth” Pain 199
As with other pain disorders, the clinical presentation is the most important part in
the diagnostic puzzle of non-odontogenic “tooth” pains. Taking time to perform a
comprehensive history taking will pay off by avoiding unnecessary diagnostic tests
and misdirected attempts at treatment. It will also lead to the true origin of the pain,
which is the desired therapeutic target.
Non-odontogenic “tooth” pains will present in a similar way as their underlying
pain-producing disorders. For this reason, it is important for dentists to have a sound
knowledge of the clinical picture of some of the most common causes of non-
odontogenic “toothache.” As a general rule, referred or projected pains will not, or
will only mildly, be affected by local treatment or provocation tests directed at the
pain site (i.e., tooth) but will rather respond more substantially to interventions
directed at the source of pain (e.g., myofascial trigger point, headache disorder,
cardiac muscle, etc.). Triggers, alleviating and aggravating factors, will also follow
the pattern of the specific underlying disorder and will differ from those typical of
true tooth pain. For instance, a “tooth” pain of cardiac origin will improve with
administration of nitroglycerin and may worsen with physical activity. A “tooth”
pain of sinus/nasal origin may be accompanied by a history of purulent nasal dis-
charge and/or subside with intranasal topical anesthetic application. None of these
two examples would be expected to respond to a local anesthetic infiltration to the
tooth where the patient perceives the pain (Table 18.1).
Table 18.1 Clinical characteristic of four of the most common causes of non-odontogenic “tooth”
pain
Pain Trigeminal Migraine
Characteristics Myofascial pain PDAP neuralgia headaches
Onset Usually associated Spontaneous or Often memorable Usually
with history of associated with first episode. associated
temporomandibular potential nerve Sudden onset. with history
disorders (TMD) injury. History May be apparently of migraine
often reveals initiated by a headaches
multiple dental non-noxious event
procedures that (i.e., wind blow,
failed to provide routine dental
sustained pain relief procedure)
Location May be felt in one or Localized, Typically Ipsilateral to
(pain site) multiple teeth and perceived in the unilateral, in the headache
change location over dentoalveolar distribution of presentation,
time (“migrating tissues in or around one trigeminal when
tooth pain”) a tooth (or location nerve branch; unilateral
of an absent tooth) maxillary (V2) or
mandibular (V3)
Quality Dull, ache, Dull, ache, Sharp, shooting, Throbbing,
pressure, burning. pressure, burning electric shock dull, ache,
Occasionally sharp pressure
with jaw function
(continued)
Pain Trigeminal Migraine
Characteristics Myofascial pain PDAP neuralgia headaches
Intensity Mild to moderate. Mild to moderate Severe Moderate to
Occasionally severe severe
with jaw function
Frequency/ Continuous or Continuous Paroxysmal Usually
duration episodic (at least 8 h/day, (less than a episodic,
15 days/month for second – up to “tooth” pain
3 months) 2 min). Usually may last
presents multiple seconds to
attacks per day hours with
pain-free
periods
between
migraine
episodes
Aggravating Jaw movement, Aggravation of Attacks may be Physical
factors function, other pain spontaneous or activity.
parafunction, or conditions triggered by Triggers may
muscle provocation (increased pain non-noxious include
tests input to the brain). stimuli (e.g., hormonal
Pain may or may light touch on cycle for
not be aggravated ipsilateral skin of women, as
by local tooth/ the face/gingiva, well as
gingiva provocation chewing, dietary and
vibration) lifestyle
factors
Alleviating Jaw rest, heat/ice, or Surgical procedures Avoiding triggers Resting in a
factors local anesthetic (surgical root-canal, may provide dark and
injection of the tooth extractions) limited relief quiet room,
affected muscle typically provide head/neck
origin temporary relief of cold
days to weeks compress,
before pain returns avoiding
to its original state migraine
or worsens. Local triggers
anesthetic
infiltration may or
may not provide
pain relief
Associated Possible jaw pain, May present altered Possible Light and/or
symptoms headaches sensation, such as ipsilateral noise
local autonomic sensitivity,
hypersensitivity features nausea and/
compared to or vomiting.
non-affected areas, Possible aura
tingling, numbness- (reversible
like sensation neurologic
disturbances,
e.g., visual
aura) and/or
ipsilateral
autonomic
signs
The frequency of all-cause persistent pain after root-canal treatment has been
reported to be 5% (63/1,267) after 3–5 years. Of those with persistent pain, 62%
(39/63) were found to be of non-odontogenic origin [3]. In a study performed in the
National Dental Practice-Based Research Network, the differential diagnosis of
persistent pain following initial orthograde root-canal treatment was evaluated [2].
Nineteen patients who had persistent pain 6 months after the procedure were exam-
ined, and more than half (10/19 = 53%) of them were diagnosed with non-
odontogenic causes for their “tooth” symptoms. The source of pain was determined
to be myofascial/TMD in nearly all of those cases (8/10 = 80%), and PDAP disorder
in the other two cases [4]. Another investigation reported that 44% (44/100) of
patients diagnosed with a non-dental orofacial pain at an endodontic practice had
previously received root-canal treatment or tooth extractions in a failed attempt to
obtain pain relief [5].
A study of 230 patients with TMD performed at a specialty clinic revealed myo-
fascial pain referral patterns to the teeth in 138 occasions, after each patient received
a comprehensive masticatory and cervical muscle palpation exam [6]. Different
types of headache disorders have also been reported to present as “tooth” pain. A
retrospective study of patients at a university-based orofacial pain clinic revealed
that 23.5% of patients with headaches reported non-odontogenic “tooth” pain refer-
ral [7]. Pain referred to the teeth was reported in 3 of 186 (1.6%) consecutive eligi-
ble patients with verified cardiac ischemic episode admitted to cardiology services
at three different hospitals [8].
Most orofacial pains affect women more frequently than man (except for cluster
headache). Central sensitization is thought to be associated with the occurrence of
heterotopic pains. Therefore, chronic pain patients with multiple pain disorders,
and/or pain that has been present for longer periods of time, would be at higher risk
for development or progression to referred and centralized pains. Psychosocial dis-
orders such as depression, anxiety, somatization, and catastrophizing may be
comorbid in orofacial pain patients.
Many of the different disorders that can present as non-odontogenic “tooth” pain
have specific underlying pathophysiologic mechanisms, and some are more com-
prehended than others. Many times the classification of the phenomena that are
thought to allow the most commonly presenting heterotopic “tooth” pains are pain
referral and projection [9].
Referred pain is perceived to be in a location innervated by a different branch of
the same nerve that innervates the source of pain or by a different nerve altogether.
This is thought to be due to central excitatory effects and conversion of neurons in
the central nervous system (CNS). Multiple peripheral neurons (primary afferents,
or first order neurons) may converge to synapse with a single second-order neuron.
Especially in situations of central sensitization and prolonged deep pain stimuli, the
origin of pain may be mistaken when processed by the CNS and perceived to be in
a normal structure (site of pain) when reaching the cortex (e.g., myofascial pain or
cardiac pain referred to the teeth). Projected pain is perceived to be in the peripheral
distribution of the affected nerve branch (e.g., trigeminal neuralgia, nerve impinge-
ment/compression).
18.5 Diagnosis, Diagnostic Criteria, and Treatment
18.5.1 Musculoskeletal Pain
18.5.1.1 Myofascial Pain with Referral

Myofascial pain is a musculoskeletal condition characterized by pain that is typi-
cally described as dull ache and the presence of localized tender areas (trigger
points) that can cause spreading or referred pain to other structures. Referral pat-
terns tend to be consistent across patients, and they have been thoroughly docu-
mented [6, 10]. Jaw muscles are known to refer pain to the teeth, and this can be
perceived as dental or intraoral pain. Muscle pain felt in the maxillary teeth is most
often referred from masseters, as well as from the temporalis and lateral ptery-
goids. The masseter muscle is also the most common source of referred muscle
pain to mandibular teeth, but lateral pterygoids, sternocleidomastoids, and anterior
digastric may also be involved.
As with muscle pain felt in the limits of the muscle structure, muscle pain referred
to teeth is mostly constant, mild to moderate in intensity, but changes with jaw move-
ment, function, and parafunction, as well as with provocation tests of the offending
muscle. Trigger points can be identified by manual palpation, as a taut band or
“knot”. Sustained firm digital pressure (~1 kg/2 lbs for approximately 5–10 s ) over
the source tender trigger point can elicit pain that duplicates the patient’s “tooth” pain
complaint. A graded response to stimuli is expected.
Diagnostic Criteria for Temporomandibular Disorders (DC-TMD)

(Schiffman et al. [11])
Myofascial Pain with Referral
History:
1 . Pain in the jaw, temple, ear, or in front of the ear
2. Pain modified by jaw movement, function, or parafunction
Exam:
1 . Confirmation of the pain location(s) in the temporalis or masseter muscle
2. Report of familiar pain with palpation of the temporalis or masseter muscle
3. Report of pain at a site beyond the boundaries of the muscle being palpated
While anesthetizing the tooth where the pain is perceived is not expected to have
a significant effect of the symptoms, performing a local anesthetic injection to the
source muscle should greatly reduce the pain. Local anesthetic infiltrations can be
used as diagnostic tests but have also been proposed as treatment for the manage-
ment of trigger points and referred muscle pain. Other treatment alternatives may
also include self-care management reducing jaw muscle overuse, physical therapy
manual techniques and modalities, dry needling/acupuncture, botulinum toxin
injections, and muscle relaxants.
18.5.2 Neuropathic Pain
Pain sensation is usually part of a physiologic process of conveying information

from actual or threatened damage to the body through normally functioning neural
structures. Conversely, neuropathic pain occurs when the pain sensing system
(somatosensory system) itself is affected by a lesion, disease, or dysfunction.
18.5.2.1 Trigeminal Neuralgia (TN)

Trigeminal neuralgia, also known as tic douloureux, is a condition affecting the tri-
geminal nerve and is characterized by episodes of short, severe, sharp, shooting,
shock-like pain. This paroxysmal pain is most often unilateral and follows the dis-
tribution of one of the three main divisions of the trigeminal nerve: ophtalmic (V1),
maxillary (V2), or mandibular (V3). In that sense, it can be felt anywhere within
that innervation territory, including teeth, and mimic a toothache [12].
Trigger areas on the skin of the face, oral mucosa, and teeth ipsilateral to the
affected trigeminal nerve branch are frequently reported, where harmless stimula-
tion such as teeth brushing, blowing wind, or light touch sets off a painful attack.
Independently from the intensity of the stimulus applied, the pain attacks are usu-
ally stereotypical and do not present a graded response. Since peripheral input is
International Classification of Headache Disorders (ICHD-3) Beta (IHS [13])

Classical Trigeminal Neuralgia
. At least three attacks of unilateral facial pain fulfilling criteria B and C
A
B. Occurring in one or more divisions of the trigeminal nerve, with no radia-
tion beyond the trigeminal distribution
C. Pain has at least three of the following four characteristics:
1. Recurring in paroxysmal attacks lasting from a fraction of a second to
2 minutes
2. Severe intensity
3. Electric shock-like, shooting, stabbing, or sharp in quality
4. Precipitated by innocuous stimuli to the affected side of the face
D. No clinically evident neurological deficit
E. Not better accounted for by another ICHD-3 diagnosis
associated with the pain episodes, local anesthetic block applied to the trigger zones
may reduce symptomatology or triggering. Thus, the clinician should be careful not
to mistakenly conclude that the complaint is odontogenic if the pain improves with
dental local anesthesia. Pain episodes can also occur spontaneously.
In some cases, when the condition appears in its first stages (pre-trigeminal neu-
ralgia), it can be difficult to diagnose due to the variability of the pain and less clas-
sic presentation. Proper diagnostic work-up may include a neurological evaluation
and magnetic resonance imaging (MRI) of the brain. For some patients, trigeminal
neuralgia is a secondary presentation of an underlying condition such as a brain
tumor or multiple sclerosis.
Education, anticonvulsant neuropathic medications (carbamazepine, oxcarbaze-
pine, gabapentin, baclofen, etc.), neurosurgery, and more recently botulinum toxin
injections have been used to treat trigeminal neuralgia. It is important to note that due
to the severe and disabling characteristic of the condition, patients may request treat-
ment for the teeth, if that is part of their pain presentation. In the absence of identifi-
able etiology, dental treatment will most likely be ineffective and unnecessary.
18.5.2.2 Persistent Dentoalveolar Pain Disorder (PDAP)

Traditionally, neuropathic orofacial pain follows a known source of injury to the
nerves of the face, teeth, or gums, due to facial trauma, surgery, dental procedures,
or infection. These can result in pain and possibly other symptoms (e.g., numbness,
tingling, hypersensitivity) that persist even after the original injury has healed.
There are also cases with a similar clinical presentation to those pains of neuro-
pathic nature, but the onset of pain is seemingly spontaneous, and no initiating event
is identified as a possible source of nerve injury [14].
Multiple nomenclatures have been used in the literature to describe persistent
orofacial pain that is not otherwise classified in another pain category, such as atypi-
cal facial pain, atypical odontalgia, and phantom tooth pain. It is unlikely that these
labels represent a single clinical entity, which creates confusion for researchers and
clinicians alike. Furthermore, these terms do not provide information on the nature
of the disorder, other than its location, and diagnostic criteria are not clear. Despite
its still unclear pathophysiologic mechanisms, the more descriptive terminology per-
sistent dentoalveolar pain disorder (PDAP) has been proposed by an expert consen-
sus group, based on ontology, and accompanied by a defined diagnostic criteria:
Diagnostic Criteria for Persistent Dentoalveolar Pain (Nixdorf et al. [14])
A. Persistenta painb
B. Localizedc in the dentoalveolar region(s)
C. Not caused by another disease or disorderd
a
Persistent meaning pain present at least 8 h per day ≥15 days or more per month for
≥3 months during
b
Pain is defined as per IASP criteria (includes dysesthesia)
c
Localized meaning the maximum pain defined within an anatomical area
d
Extent of evaluation nonspecified (dental, neurological examination +/−) imaging, such as
intraoral, CT, and/or MRI)
18.5.2.3 Neuritis
Innervation to the mouth and teeth can be irritated by local inflammation, causing
what is generally called neuritis [1]. The source of insult could be physical (e.g.,
compression during implant placement), chemical (e.g., extravasation of endodon-
tic irrigation solution, medicaments, or filling material), or biological (e.g., herpes
simplex, herpes zoster [shingles], or bacterial infection). An acute herpes infection
or reactivation of dormant virus lodged in the trigeminal ganglion may cause pain
in the distribution of the nerve days or weeks prior to outbreak of vesiculobullous
lesion on the skin or mucosa. Some cases may not present these lesions, posing a
greater diagnostic challenge, but painful trigeminal neuropathy attributed to acute
herpes zoster (viral neuritis) should be considered in the differential diagnosis of
patients with a history of primary varicella zoster infection (chicken pox).
18.5.2.4 Neuroma
Nerve injury may also result in the development of a traumatic neuroma, a disorga-
nized proliferation of the severed nerve tissue, which can sometimes be painful. In
the orofacial region, most cases present in the soft tissues around the mental fora-
men, lips, and tongue, but intraosseous lesions have also been reported. These have
been proposed to be a potential explanation in cases of persistent pain after apparent
healing post-extraction or pulpectomy.

Painful Trigeminal Neuropathy Attributed to Acute Herpes Zoster
A. Unilateral head and/or facial pain lasting >3 months and fulfilling crite-
rion C
B. Either or both of the following:
1. Herpetic eruption has occurred in the territory of a trigeminal nerve
branch or branches.
2. Varicella zoster virus DNA has been detected in the CSF by poly-
merase chain reaction.
C. Evidence of causation demonstrated by both of the following:
1. Pain preceded the herpetic eruption by <7 days.
2. Pain is located in the distribution of the same trigeminal nerve branch
or branches.
D. Not better accounted for by another ICHD-3 diagnosis
Post-herpetic Trigeminal Neuropathy
A. Unilateral head and/or facial pain persisting or recurring for ≥3 months
and fulfilling criterion C
B. History of acute herpes zoster affecting a trigeminal nerve branch or branches
C. Evidence of causation demonstrated by both of the following:
1. Pain developed in temporal relation to the acute herpes zoster.
2. Pain is located in the distribution of the same trigeminal nerve branch
or branches.
D. Not better accounted for by another ICHD-3 diagnosis
When a secondary cause for the pain is present, treatment usually starts by
removing or addressing the etiologic agent (nerve decompression, antiviral medica-
tion) and can also include anti-inflammatory medications such as corticosteroids.
Response to local anesthetic blocks may help to determine the level to which the
pain is more peripheral or central, since central pain will not be responsive to a
peripheral nerve block. Typically, the longer the pain has been present providing
input to the pain processing centers in the brain, the greater is the tendency of cen-
tral sensitization changes occurring. Oral medications that regulate nerve function
(e.g., amitriptyline, gabapentin, pregabalin) are the first-line treatment neuropathic
pain, and topical medications may be considered when there is a significant periph-
eral component.
18.5.2.5 Post-Herpetic Trigeminal Neuropathy

Although less commonly reported as a source of pain presenting in the teeth, post-
herpetic neuralgia in the orofacial region, characterized by persistent pain following
a herpes zoster reactivation (shingles), may also be a source of non-odontogenic
“tooth” pain of neuropathic origin. It is also known as post-herpetic neuralgia, how-
ever, the term neuralgia is avoided in this case since it typically refers to paroxysmal
pains, while this pain condition tends to present as constant.
18.5.3 Neurovascular Pain
Primary headaches, such as migraines, cluster headaches, and other trigeminal auto-
nomic cephalalgias, have been reported to present as “toothache” [15]. Neurovascular
disorders are thought to be associated with transient alterations in the function and
sensitization of the trigeminal nerve and vasculature of the head. The pain is referred
and felt in somatic structures of the head, such as the forehead, temples, behind the
eyes, sinuses, and sometimes the teeth. The episodes of pain can be spontaneous,
severe, and throbbing and have periods of remission. Odontogenic toothache can
also wax and wane but tends to leave some level of low-grade background pain. In
contrast, patients with headaches presenting as “tooth” pain will typically have
pain-free periods between episodes. Attention to the timing, duration, and associ-
ated features will help to differentiate the underlying disorder. Migraines, affecting
approximately 18% of females and 6% of males, are likely the most common head-
ache disorder to present as “tooth” pain.
Trigeminal autonomic cephalalgias such as cluster headache are rare unilateral
neurovascular disorders. Pain attacks are accompanied by ipsilateral autonomic fea-
tures on the face, such as facial erythema, periorbital swelling, eyelid edema, tear-
ing, conjunctival injection, nasal congestion, rhinorrhea, ptosis, or miosis. Treatment
differs according to the diagnosis and often includes medications, diet changes, and
lifestyle modification.

Migraine Without Aura
. At least five attacks fulfilling criteria B–D
A
B. Headache attacks lasting 4–72 h (untreated or unsuccessfully treated)
C. Headache has at least two of the following four characteristics:
1. Unilateral location
2. Pulsating quality
3. Moderate or severe pain intensity
4. Aggravation by or causing avoidance of routine physical activity (e.g.,
walking or climbing stairs)
D. During headache at least one of the following:
1. Nausea and/or vomiting
2. Photophobia and phonophobia
Migraine with Aura
. At least two attacks fulfilling criteria B and C
A
B. One or more of the following fully reversible aura symptoms:
1. Visual
2. Sensory
3. Speech and/or language
4. Motor
5. Brainstem
6. Retinal
C. At least two of the following four characteristics:
1. At least one aura symptom spreads gradually over 5 min, and/or two or
more symptoms occur in succession.
2. Each individual aura symptom lasts 5–60 min.
3. At least one aura symptom is unilateral.
4. The aura is accompanied, or followed within 60 min, by headache.
D. Not better accounted for by another ICHD-3 diagnosis, and transient isch-
emic attack has been excluded.
Cluster Headache
. At least five attacks fulfilling criteria B–D
A
B. Severe or very severe unilateral orbital, supraorbital, and/or temporal pain
lasting 15–180 min (when untreated)
C. Either or both of the following:
1. At least one of the following symptoms or signs, ipsilateral to the
headache:
(a) Conjunctival injection and/or lacrimation
(b) Nasal congestion and/or rhinorrhoea
(c) Eyelid edema
(d) Forehead and facial sweating
(e) Forehead and facial flushing

(f) Sensation of fullness in the ear
(g) Miosis and/or ptosis
2. A sense of restlessness or agitation
. Attacks have a frequency between one every other day and eight per day
D
for more than half of the time when the disorder is active.
Paroxysmal Hemicrania
. At least 20 attacks fulfilling criteria B–E.
A
B. Severe unilateral orbital, supraorbital, and/or temporal pain lasting
2–30 min.
C. At least one of the following symptoms or signs, ipsilateral to the pain:
1. Conjunctival injection and/or lacrimation
2. Nasal congestion and/or rhinorrhoea
3. Eyelid edema
4. Forehead and facial sweating
5. Forehead and facial flushing
6. Sensation of fullness in the ear
7. Miosis and/or ptosis
D. Attacks have a frequency above five per day for more than half of the time.
E. Attacks are prevented absolutely by therapeutic doses of indomethacin.
F. Not better accounted for by another ICHD-3 diagnosis.
Short-Lasting Unilateral Neuralgiform Headache Attacks
. At least 20 attacks fulfilling criteria B–D.
A
B. Moderate or severe unilateral head pain, with orbital, supraorbital, tempo-
ral, and/or other trigeminal distribution, lasting for 1–600 s and occurring
as single stabs, series of stabs, or in a sawtooth pattern.
C. At least one of the following cranial autonomic symptoms or signs, ipsi-
lateral to the pain:
2. Nasal congestion and/or rhinorrhoea
3. Eyelid edema
D. Attacks have a frequency of at least one a day for more than half of the
time when the disorder is active.
E. Not better accounted for by another ICHD-3 diagnosis.
Hemicrania Continua
. Unilateral headache fulfilling criteria B–D
A
B. Present for >3 months, with exacerbations of moderate or greater intensity

1. At least one of the following symptoms or signs, ipsilateral to the headache:
(b) Nasal congestion and/or rhinorrhoea
(c) Eyelid edema
2. A sense of restlessness or agitation or aggravation of the pain by movement
D. Responds absolutely to therapeutic doses of indomethacin
18.5.4 Referred Pain from Regional or Distant Pathology
18.5.4.1 Cardiac Pain

Heart problems such as angina pectoris or acute myocardial infarction refer pain to
the shoulder, arm, and even to the jaw or teeth. As in tooth pulp pain which presents
in a visceral-like pattern, cardiac “toothache” presents as diffuse and difficult to
localize, described as aching or sometimes pulsatile [16]. Although it is usually felt
in the lower left jaw, it can also be bilateral. Occasionally, it is associated with chest
pain, but it can also present as a sole symptom. When a “toothache” has a cardiac
origin, it usually increases with exercise and decreases with cardiac medication
such as nitroglycerin tablets, but is not affected by local provocation or local anes-
thetic blocks of the teeth. After ruling out dental pathology, immediate referral to
medical care is needed, and treatment is directed to the underlying heart problem.
Other thoracic structures have also been implicated in non-odontogenic “tooth”
pain reports, such as in cases of lung cancer and diaphragmatic pain.
18.5.4.2 Sinus/Nasal Pain

Problems in the maxillary sinuses and/or paranasal mucosa can refer pain to the
maxillary teeth [17]. The pain is usually felt in several teeth and is described as pres-
sure, fullness, dull, aching, or throbbing. Sometimes, it is associated with pressure
below the eyes and can increase with lowering the head, putting pressure over the
sinuses, coughing, or sneezing. Tests performed on the teeth such as cold, chewing,
and percussion can exacerbate pain from sinus origin. A history of an upper respira-
tory infection, purulent nasal discharge, nasal congestion, or obstruction should
lead to suspicion of a sinus-related “toothache”. Further diagnosis and treatment
should be provided by an otolaryngologist. Diagnostic tests such as visual nasal
exam, sinus X-rays, or MRI may be useful to confirm this condition. While the pain
does not subside with dental anesthesia, application of intranasal topical anesthesia
to the offending area should eliminate the pain. Treatment options include antihis-
tamines, decongestants, and antibiotics.
18.5.4.3 Pain Related to Neoplasias and Other Lesions in the Head

and Neck
Tumors and other space-occupying lesions anywhere near the course of the trigemi-
nal nerve have the potential to cause compression or impingement [18]. And any
trigeminally innervated somatic structures can also cause referred pain to the mouth
and teeth [19]. The symptom presentation can be highly variable, but trigeminal
sensory deficit, paresthesia, or pain in the distribution of the affected branch can be
present. When the source disorder is intracranial, headache is a common complaint.
Depending on the extent and the location of the lesion, there may be also non-
trigeminal neurological deficits.
Due to the highly variable symptom presentation, a comprehensive cranial nerve
examination, as well as advanced regional imaging techniques such as computed
tomography (CT) or magnetic resonance imaging (MRI), may be needed, especially
for patients with a history of cancer. Tumors in the pharyngeal wall, maxillary sinus,
and the jaw have been reported to present as “tooth” pain. Vascular disorders, such
as carotid artery dissection, aneurisms, and arteritis, have also been involved in
cases of non-odontogenic “tooth” pain. The dental symptoms may be accompanied
by systemic symptoms, such as weight loss, malaise, or fatigue. Although possible,
these problems are very rare and adequate referral for further diagnosis and treat-
ment is indicated.
18.5.5 Pain Disorders Related to Psychological Factors
Psychosensory disturbances in the category of somatoform disorders are character-

ized by somatic complaints and symptoms that are not explained by a physical
cause but could be related to psychological factors. Patients with psychogenic pain,
differently than in cases of malingering behavior, do not consciously fabricate
symptoms to achieve a certain benefit. However, true psychogenic pain is an
extremely rare diagnosis of exclusion when accounting for pains of any kind. To
consider that this pain would present in the teeth is even more unlikely. Therefore,
this pain category is probably highly overdiagnosed, when the true source of pain
has not been yet identified, and psychosocial factor overlay creates a “colorful”
symptom presentation.
Pain disorders are often comorbid with mental disorders (i.e., anxiety, depres-
sion, catastrophizing, somatization), and those can contribute to the pain experi-
ence. Nevertheless, a causal link between psychological factors and “toothaches” of
non-dental origin has not been established. A consultation with a health psycholo-
gist or psychiatrist may shed light as to possible cognitive-behavioral and/or psy-
chosocial contributing factors to the persistent pain experience.
References
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2016. p. 684.
2. Yatani H, Komiyama O, Matsuka Y, et al. Systematic review and recommendations for non-
odontogenic toothache. J Oral Rehabil. 2014;41(11):843–52.
3. Vena DA, Collie D, Wu H, et al. Prevalence of persistent pain 3 to 5 years post primary root
canal therapy and its impact on oral health-related quality of life: PEARL network findings.
J Endod. 2014;40(12):1917–21.
4. Nixdorf DR, Law AS, John MT, et al. Differential diagnoses for persistent pain after root
canal treatment: a study in the national dental practice-based research network. J Endod.
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5. Linn J, Trantor I, Teo N, Thanigaivel R, Goss AN. The differential diagnosis of toothache from
other orofacial pains in clinical practice. Aust Dent J. 2007;52(1 Suppl):S100–4.
6. Wright EF. Referred craniofacial pain patterns in patients with temporomandibular disorder.
J Am Dent Assoc. 2000;131(9):1307–15.
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Pain Headache. 2014;28(1):6–27.
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Trigeminal Neuropathic Pain
and Orofacial Neuralgias 19
David A. Sirois and Teekayu P. Jorns
Pearls of Wisdom
• In a suspected trigeminal neuralgia scenario, it is important to rule out
intracranial lesions (such as a mass or demyelination) as a source of pain
through imaging. Intracranial lesion may be suspected if the patient is
young, and there are neurologic deficits (e.g., loss of sensation, numb-
ness) and loss of other sensory function including hearing, sight, or
smell.
• Neuropathic orofacial pain is often accompanied by other pain disor-
ders such as myofascial pain or dental pulpitis. Management of any
related disorders that contribute to hypersensitivity of the trigeminal
nerve may be necessary to obtain improved relief from pharmacologi-
cal management.
• A multidisciplinary pain team approach is helpful to facilitate success in
complex neuropathic pain patients with multiple pain disorders and con-
tributing factors.
D.A. Sirois, DMD, PhD

Department of Oral & Maxillofacial Pathology, Radiology and Medicine,
New York University College of Dentistry, New York, USA
Department of Neurology, New York University School of Medicine,
New York City, NY, USA
T.P. Jorns, DDS, MDSc, PhD (*)
Department of Oral Biology, Faculty of Dentistry, Khon Kaen University,
Khon Kaen, Thailand
e-mail: teepla@kku.ac.th

DOI 10.1007/978-3-319-51508-3_19
214 D.A. Sirois and T.P. Jorns
Trigeminal neuropathic pain disorders refer to chronic orofacial pain conditions

maintained primarily by neuropathic mechanisms (due to nervous system injury or
dysfunction) and not nociceptive mechanisms (inflammatory). All of the conditions
described in this section exhibit varying degrees of nervous system sensitization and
hyperexcitability as the primary mechanism for sustained pain. The neuropathic
disorders in this category include the classic cranial neuralgias (trigeminal, glosso-
pharyngeal, and post-herpetic), traumatic trigeminal neuropathic pain, trigeminal
neuropathic pain of undetermined origin, and primary burning mouth syndrome
(stomatodynia). Non-dental tooth pain and burning mouth syndrome are addressed
more extensively in Chaps. 18 and 20 of this clinical guidebook, respectively.
These disorders share the common features of chronicity (continuous or inter-
mittent) and loss of typical stimulus-response features seen in nociceptive inflam-
matory pain. That is, pain may be spontaneous or result from non-painful stimulation
and reach magnitudes and qualities inconsistent with a provoking stimulus. It is
imperative that the clinician not be misled that the site of the pain is necessarily the
source of the pain, leading to misdirected therapy at the site of the pain experience
(i.e., endodontia or exodontia).
While a universally accepted disease classification system for trigeminal neuro-
pathic pain has not been established, there is centainly consensus on broad issues of
these diagnoses and their treatment. This chapter classifies the disorders according
to the diagnostic guidelines of the International Classification of Headache Disorders
(ICHD 2013) [1] and the Neuropathic and Orofacial Pain Special Interest groups of
the International Association for the Study of Pain [2].
• Trigeminal Neuralgia (TN)

–– Classical Trigeminal Neuralgia (CTN)
Unilateral, brief, sharp, lancinating pain in the trigeminal nerve distribution,
usually in the second or third division, with severe intensity and pain-free
intervals in the absence of any underlying intracranial pathological condition
such as a mass or demyelination; often triggered by light (non-painful) touch
(i.e., trigger point). Paroxysmal pain is the main compliant, but it may be
accompanied by continuous pain. The duration of pain attacks can change
over time and become more prolonged as well as severe.
–– Secondary Trigeminal Neuralgia (STN)
Clinical presentation as described for primary trigeminal neuralgia but with
an identified intracranial pathological condition such as a mass or demyelin-
ation (i.e., multiple sclerosis) or nonneoplastic cysts (i.e., epidermoid or
arachnoid cysts). Most of STN patients are younger than expected for cases of
TN and develop subtle or frank neurological deficits.
• Glossopharyngeal Neuralgia (GN)
Severe, unilateral, brief, sharp, lacinating pain in the glossopharyngeal nerve dis-
tribution (in the ear, base of the tongue, tonsillar fossa, and/or beneath the angle
of the jaw) with variable frequency and pain-free intervals in the absence of any
underlying intracranial pathological condition such as a mass or demyelination.
19 Trigeminal Neuropathic Pain and Orofacial Neuralgias 215
Swallowing, talking, and coughing commonly provoke it. Similar to trigeminal

neuralgia, glossopharyngeal neuralgia may be primary or secondary in nature,
and these two disorders can occur together.
• Post-herpetic Neuralgia (PHN)
Continuous burning pain following a known history of painful skin rashes/
blisters (shingles) in the trigeminal nerve distribution after a varicella zoster viral
infection (herpes zoster).
• Painful Traumatic Trigeminal Neuropathy (PTTN)
Follows known injury to the trigeminal nerve, such as oral or sinus surgery, or
trauma to the orofacial region. Usually presenting as a continuous burning, stinging,
or aching pain in the territory of the injured nerve and may additionally have brief
paroxysmal sharp pain superimposed on the continuous, background pain. Non-
painful symptoms may include pins-and-needles sensation, tingling, or numbness.
If the injury involves the lingual nerve, there may be diminished, distorted, or phan-
tom taste and unilateral burning sensation of the tongue on the affected side.
• Trigeminal Neuropathic Pain of Undetermined Origin (TNPUO)
Similar in quality to trigeminal neuropathic pain but without antecedent nerve or
tissue injury, and without evidence of related intracranial or local pathology. This
is the pain most likely to spread or move to multiple (including bilateral) trigemi-
nal nerve distributions. While this condition has historically been referred to as
atypical odontalgia, atypical facial pain, and/or phantom tooth pain, the term
trigeminal neuropathic pain of undetermined origin more accurately describes
the condition and avoids presumptions of etiology.
• Primary Burning Mouth Syndrome (BMS) or Stomatodynia
Chronic, continuous intraoral burning sensation not associated with an identifi-
able mucosal abnormality such as candidiasis, trauma, or ulceration and with no
underlying contributing systemic illness such as diabetes mellitus or anemia.
Burning sensation occasionally may be associated with dysgeusia.
• Pain – while all of the neuropathic face pains run a chronic course, it is important to
distinguish the temporal patterns, distribution, quality, and provocation since these
characteristics cannot only distinguish neuropathic from nociceptive pain but can
also discriminate among the neuropathic pain subtypes. Table 19.1 below summa-
rizes the classical pain characteristics among the neuropathic pain disorders; cer-
tainly there can and will be exceptions to these generalizations particularly following
invasive treatments or if there is deterioration of the pain condition over many years.
Unlike inflammatory, nociceptive pain which will demonstrate consistent hyperal-
gesia and allodynia (increased pain perception to a painful stimulus or pain percep-
tion to a non-painful stimulus, respectively), neuropathic pain may be constant in
nature without provocation or paroxysmal in nature without reliable response (i.e.,
unexplained pain-free intervals). Classical TN lasts for seconds to minutes and has
pain free intervals – clearly different from continuous forms of neuropathic pain –
and is not reliably provoked by touch – clearly different from nociceptive pain.
Table 19.1 Comparison of clinical characteristics of orofacial neuropathic pain

Classical cranial neuralgias Nonclassical neuralgias
Pain features CTN STN GN PHN PTTN TNPUO BMS
Quality:
Sharp, shooting, stabbing +++ +++ +++ + + +
Burning, stinging + + + +++ ++ ++ +++
Aching ++ ++
Paresthesia or anesthesia + + + +
Trigger:
Light touch or movement +++ ++ ++ + + +
Spontaneous + + + ++ +++ +++ +++
Timing:
Continuous +++ +++ +++ +++
Intermittent + + + + +
Paroxysmal +++ ++ +++
Location:
Unilateral +++ ++ +++ +++ +
Multifocal ++ + +++ +
Neurological deficit +++ +
History of trauma or pathogen- +a +++
related infection
a
Related to herpes zoster infection. Legend: +++ most likely, ++ less likely, + possible, PTN pri-
mary trigeminal neuralgia, STN secondary trigeminal neuralgia, GN glossopharyngeal neuralgia,
PHN post-herpetic neuralgia, PTTN painful traumatic trigeminal neuropathic, TNPUO trigeminal
neuropathic pain of undetermined origin, BMS burning mouth syndrome
• Neurologic deficits such as anesthesia, hypesthesia, motor weakness, loss of cra-

nial reflexes (corneal blink, gag), diminished taste, paresthesia, or asymmetry of
the face, tongue, or palate may be present following peripheral nerve injury.
When focal deficits are present in the absence of an antecedent injury, suspicion
is increased for intracranial mass or demyelinating disease. Bilateral facial pain
is more common in secondary TN due to multiple sclerosis than in primary tri-
geminal neuralgia.
• Muscle tenderness secondary to myofascial pain can occur in some patients with
neuropathic pain, particularly if there is guarding, splinting, or unilateral chew-
ing in an attempt to avoid painful stimuli.
• Other associated signs and symptoms may occur including dizziness, tinnitus,
and plugged ears, tearing, nasal congestion.
• Classical Trigeminal Neuralgia (CTN) [3]

–– Accounts for the vast majority (>90%) of TN cases (compared to secondary TN)
–– Increased risk with age: most patients over age 50
–– Overall incidence of 5.7 for women and 2.5 for men per 100,000 people
–– Etiology: neurovascular compression of the trigeminal nerve, most frequently
by the superior cerebellar artery at the root entry zone
• Secondary Trigeminal Neuralgia (STN) [3]

Can be secondary to:
–– Multiple sclerosis (MS) affects approximately 1 in 700 people, with an estimated
US prevalence of 250,000–500,000. Approximately 1–2% of patients with MS
develop TN (about ten new cases per year and cumulative total of approximately
4,000–5,000 people). Only about 3% of patients with TN have MS.
–– An intracranial mass such as a tumor or aneurysm (excluding vascular com-
pression from cerebellar arteries) is accounting for 10–13% of all TN cases.
• Glossopharyngeal Neuralgia (GN) [4]
–– Little available data on incidence, though estimated to be <1:100,000.
–– Like trigeminal neuralgia, it affects most often people over age 50.
–– No reliable data on ratio female/male prevalence.
–– Vascular compression may play a role in the primary form of GN, though the
data is not as compelling as for primary TN.
–– MS or intracranial mass affecting the GN may lead to hyperexcitability simi-
lar to that seen in TN.
• Post-herpetic Neuralgia (PHN) [5, 6]
–– Approximately 1,000,000 new cases of varicella zoster virus (shingles) in the
United States each year; 20% in the trigeminal distribution and 80% in the
spinal distribution.
–– Twenty percent of individuals with shingles go on to develop PHN, and the
risk increases with age: 50% of all PHN cases are over age 60, and 75% of all
PHN cases are over age 70.
–– Cumulative prevalence of PHN exceeds one million.
–– Viral neuritis leading to axonal degeneration and death, with subsequent
altered CNS sensory processing.
• Painful Traumatic Trigeminal Neuropathy (PTTN) [7–9]
–– Between 1% and 5% of lower third molar extractions result in nerve injury, of
which approximately one-third of injuries are permanent.
–– The estimated incidence of inferior alveolar nerve injury following a mandibu-
lar block is 1:25,000–1:50,000 – less than or equal to one event per dentist
practice lifetime. In addition to mechanical injury during the injection, local
anesthetic neurotoxicity has also been implicated, with prilocaine and articaine
having higher risk potential than lidocaine, bupivicaine, or mepivicaine.
–– Three reports have estimated the incidence of post-endodontic neuropathic
pain to range from 1% to 3%.
–– Known injury to the trigeminal nerve or tissue in its innervation territory.
–– While most patients recover from therapeutic (i.e., surgical) tissue injury, some do
not and instead have a neuropathic response. Indeed, there is emerging data from
the human genome project that suggests genetic risk factors for neuropathic pain.
• Trigeminal Neuropathic Pain of Undetermined Origin
–– No reliable data on prevalence or incidence, though most authorities agree it
is more common than PTTN and that women are affected at least twice as
often as men.
–– The average age of onset (age 35) is much earlier than for primary TN (greater
than age 50).
• Primary Burning Mouth Syndrome (Stomatodynia)

–– Affects 0.7–2% of the population, increasing with age (most patients over
age 50).
–– Women are more frequently affected than are men, and the relative proportion
is between 3 and 20 females for each male, depending on the study.
–– Excluding burning mouth syndrome secondary to identified local or systemic
pathology, primary burning mouth is viewed as a neuropathic pain condition
that may result from alterations in the balance of general and special somatic
afferent innervation and possible disinhibition (and hyperexcitability) of noci-
ceptive afferents.
• The pathophysiology of classical trigeminal neuralgia is not known. However,

local compression from nearby cerebellar blood vessels at the trigeminal root
entry zone is widely held as the underlying cause in most cases. Following what-
ever initiating event for the pain (demyelination, trauma, compression), the nerve
becomes hyperexcitable and results in the paroxysmal pain of CTN [10]. The
ignition hypothesis is a provocative explanation recently put forth to explain the
unusual behavior of the trigeminal primary afferent in CTN. The model explains
how periodic and synchronized spike activity can arise within the nerve and pro-
duce the physiological and psychophysical phenomena observed in TN.
• The pathophysiology of PTTN is consistent with known events following nerve
injury that lead to CNS sensitization, including decreased response thresholds
and increased response magnitudes of affected neurons, expansion of receptive
fields, loss of modality properties, and increased spontaneous activity; these pat-
hoophysiological events result in spontaneous and continuous pain as well as the
unusual spread and referral of pain [11].
• The understanding of the biophysical events leading to pathological neuronal
hyperexcitability and pain is rapidly expanding. The emerging picture of a
dynamically maintained neural network that can change phenotypic and func-
tional properties as a result of past events (injury, excitation, etc.) is driving the
development of novel classes of analgesics that will focus on reducing the patho-
logical excitability by interacting at key receptor and second messenger system
levels. This pharmacologic innovation will lead in the very near future to an
expanded inventory of exciting and effective drugs for neuropathic pain.
19.5 Diagnostic Criteria and Diagnostic Tests
The diagnosis of trigeminal neuropathic pain, including TN can be achieved by a

careful history taking, i.e., recent history of shingles, trauma, surgery, or medication
that may lead to the onset of pain. All of the conditions in this chapter and its diag-
nostic criteria have been described in the International Classification of Headache
Disorders 3rd edition (beta version, 2013) [1]. However, the following are other
investigations needed for trigeminal neuropathic pain patients:
• Hematological and biochemical tests

Blood tests are important in patients with burning mouth in order to rule out its
primary causes. In TN and other trigeminal neuropathic pain, blood tests are not
required for diagnosis but are important in baseline monitoring for patients on
future drug therapy.
• Trigeminal nerve sensory testing
May indicate underlying neurological deficits and play a role in differentiating
STN from CTN
• Imaging
Neuroimaging is useful to differentiate between CTN and STN.
When MS plaque, mass, aneurysms, or intracranial vessel compression is sus-
pected, MRI scan of the brain is suggested.
• Psychosocial assessment
The psychological assessment of the patient with chronic pain is essential – not
because it is the cause of the patient’s pain (this rarely is the case) but because
patients with chronic pain will suffer, and demoralization, depression, and dis-
ability are not unexpected. Indeed, successful treatment must address these
issues, and recent work has indicated that these characteristics of the patient with
chronic pain are strong predictors of treatment outcome.
Orofacial neuropathies or neuralgias are chronic illnesses with the likelihood for
many years of pain of varying intensity and frequency. Therefore, treatment should
not only focus on reducing the pain experience but also improving the quality of life
by addressing (with the aid as needed of behavioral and physical medicine health
providers) any associated psychological distress (e.g., poorly controlled depression
and/or anxiety) and disability [12].
• Trigeminal Neuralgia [13, 14]

–– Carbamazepine is the first-line therapy and is highly efficacious in TN. Recent
data implicate the human leukocyte antigen (HLA) allele B*1502 as a marker
for carbamazepine-induced Steven-Johnson syndrome and toxic epidermal
necrolysis in Asian population, in which this allele is seen in high frequency.
The United States Food and Drug Administration (FDA) as well as other pub-
lic health authorities in Asia have recommended genotyping all Asians for the
allele before starting this medication [15]. Alternatively, it’s derivative, oxcar-
bazepine, can also be tried as it is well tolerated with similar efficacy. In
refractory cases, gabapentin can also be used [16, 17].
–– Surgical intervention should be considered in medication-resistant cases. The
procedural remedies appear to provide significant relief for approximately
75% of patients over a 15 year period. Microvascular decompression (MVD)
is recommended as it is the only nondestructive method for the treatment of
TN and involves displacement of the offending cerebellar blood vessel(s)

away from the trigeminal root in the cerebellopontine angle. The alternative
procedures are all destructive percutaneuous techniques to reduce nerve excit-
ability and pain including radiofrequency thermocoagulation, percutaneous
glycerol rhizotomy, and balloon microcompression [18].
• Painful Traumatic Trigeminal Neuropathy and Pain of Undertermined Origin [19–21]
–– Tricyclic antidepressants: amitriptyline, nortriptyline
–– Anticonvulsants: gabapentin, pregabalin
–– Topical medications: capsaicin, lidocaine, and doxepin present a challenge
when used intraorally (adherence, penetration; enhanced by adhesives and
stents) and also present a compliance challenge. An advantage is the lack of
systemic side effects and drug interactions.
• Post-herpetic Neuralgia [22]
–– Recognizing the significant increased risk for PHN in patients over age 60
who develop shingles is critical and should lead to immediate combination
antiviral therapy and a tricyclic antidepressant – this can reduce by 50% the
risk for developing PHN. Administration of prednisolone during the acute
phase, along with antiviral therapy (famcyclovir, valacyclovir), reduces the
neuritis and pain of acute shingles.
–– Tricyclic antidepressants: nortriptyline, amitriptyline, desipramine
–– Anticonvulsants: gabapentin, pregabalin
–– Topical medications: lidocaine 5% transdermal patch
–– Opiods: long-acting, sustained release (oxycodone) proven efficacy
• Burning Mouth Syndrome [23, 24]
–– Topical and intraoral medications: lidocaine (topical), clonazepam (in troches
or topical)
–– Tricyclic antidepressants: amitriptyline, nortriptyline
Target doses for selected medications for trigeminal neuropathic pain and orofa-
cial neuralgias are provided in Table 19.2. Medications may be prescribed alone but
commonly are combined to achieve adequate pain relief. The various combinations
and management strategies are beyond the scope of this monograph, and the reader
is encouraged to seek consultation with an oral medicine, orofacial pain, or neurolo-
gist specialist for complex pain conditions.
• Treatment goals are pain relief, restore patient’s function, and improve quality of
life. Many of the medications available to treat neuropathic pain have significant
adverse and side effects, requiring a thorough understanding of their pharmacol-
ogy and medical monitoring.
• A stepwise management approach for classical and nonclassical trigeminal neu-
ropathic pains and orofacial neuralgias is summarized below in Fig. 19.1, which
includes pharmacological and non-pharmacological therapies.
Table 19.2 Target doses for selected medications for neuropathic pains or neuralgias
Generic drug name Trade name in US Class Target dose rangea
Carbamazepine Tegretol Anticonvulsant 200–600 mg PO bid
Carbamazepine XR Tegretol XR Anticonvulsant 200–400 mg PO bid
Carbamazepine SR Carbatrol Anticonvulsant 200–400 mg PO bid
Oxcarbazepine Trileptal Anticonvulsant 300–600 mg PO bid
Gabapentin Neurontin Anticonvulsant 300–3600 mg PO tid
Valproate Valproic acid Anticonvulsant 250–500 mg PO bid
Lamotrigine Lamictal Anticonvulsant 50–200 mg PO bid
Tiagabine Gabitril Anticonvulsant 2–4 mg PO bid-qid
Topiramate Topamax Anticonvulsant 50–100 mg PO bid
Baclofen Lioresal Muscle relaxant 10–20 mg PO tid
Clonazepam Klonopin Benzodiazepine 0.5–2 mg PO qhs
Amitriptyline Elavil Tricyclic antidepressant 10–75 mg PO qhs
Nortriptyline Pamelor Tricyclic antidepressant 10–75 mg PO qhs
Imipramine Tofranil Tricyclic antidepressant 10–50 mg PO qhs
Desipramine Norpramin Tricyclic antidepressant 10–75 mg PO qhs
Mexiletine Mexitil Antiarrhythmics 150–300 mg PO qd
Pregabalin Lyrica Anticonvulsants 75–600 mg PO bid
a
Range going from a initial dose to titrate up and reach therapeutic effect before evaluating out-
come. Side effects, adverse effects, and combination strategies are described in selected publica-
tions listed in the references section
Traumatic trigeminal
neuropathic pain &
Primary pain of
burning mouth undetermined origin
Trigeminal
neuralgia syndrome
First line Second line First line First line Second line
therapy therapy therapy therapy therapy
Medications: Baclofen Clonazepam Gabapentin Clonazepam
Carbamazepine Valproate TCAs: Amitriptyline Baclofen
Carbamazepine SR Lamotrigine Amitriptyline Nortriptyline Lamotrigine
Oxcarbazepine Topirimate Nortriptyline Imipramine Topirimate
Gabapentin Imipramine Desipramine Mexiletine
Clonazepam
Procedures: + TCAs
MVD
Gamma knife NERVE BLOCK
RF neurolysis TOPICALS
Glycerol rhizotomy
Alcohol neurolysis Third line
Balloon therapy
Decompression Opiods
Fig. 19.1 Flow chart with the stepwise management of classical and nonclassical trigeminal neu-
ropathic pains and orofacial neuralgias
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Burning Mouth Syndrome
20
Miriam Grushka and Nan Su
Pearls of Wisdom
• Burning mouth syndrome (BMS) is an idiopathic chronic pain condition
that remains difficult to both diagnose and treat.
• Various classifications/taxonomy for BMS to date have not led to specific
treatments or provided a prognosis for each classification, suggesting that
current knowledge are inadequate to properly understand the pathogenesis
of BMS for each classification.
• Diagnosis of BMS has been facilitated with blood tests, taste tests, salivary
flow collection, and medical imaging studies. Here, we review how to
diagnose and treat BMS.
20.1 Introduction
Burning mouth syndrome (BMS) is a chronic pain condition often characterized by

burning of the oral mucosa in the absence of clinically notable mucosal changes and
affects primarily peri- and postmenopausal women [1]. In the past, it has been
referred to as scalded mouth syndrome, stomatodynia, glossodynia, glossalgia, oral
dysesthesia, glossopyrosis, and sore tongue, which has led to confusion in diagnosis
and treatment [1, 2]. The International Association for Study of Pain (IASP) defines
BMS as characterized by “burning oral sensation or pain, unremitting while in the
M. Grushka, MSC, DDS, PhD (*)

William Osler Health Centre, 974 Eglinton Ave W., Toronto, ON, Canada
Norman Bethune College of Medicine, Jilin University, Changchun, China
e-mail: miriamgrushka@gmail.com
N. Su, BSc, MBBS
Norman Bethune College of Medicine, Jilin University, Changchun, China

DOI 10.1007/978-3-319-51508-3_20
224 M. Grushka and N. Su
absence of objective clinical changes in the oral mucosa,” and the International
Headache Society defined it as “an intraoral burning sensation for which no medical
or dental cause can be found” [2].
Several of the classifications of BMS proposed are included:
• Lamey and Lewis (1996) classified BMS into three subtypes based on pain pat-
tern and intensity. In this classification, type 1 was described as daily pain that
progresses in intensity over the day, type 2 was described as daily constant pain
present throughout the day, and type 3 was described as intermittent burning
that presents only on some days and can also affect unusual sites such as the
neck [1, 3].
• Scala et al. (2003) classified BMS into two categories depending on etiol-
ogy: primary (essential/idiopathic) when systemic or local causes cannot be
identified and secondary, resulting from local, systemic, or psychological
factors [4].
• Jääskeläinen et al. (2012) further classified primary BMS into three sub-
groups based on pathology. The first subgroup is characterized by focal
peripheral small diameter fiber neuropathy; the second subgroup is charac-
terized by subclinical trigeminal neuralgia; and the third subgroup is charac-
terized as having central involvement including hypofunction of dopaminergic
neurons [5].
It should be noted that there appear to be no general consensus among researchers

and clinicians about which classification system is most useful clinically and none of
the classification appear to be a widespread use among patient populations.
20.2 Epidemiology and Etiology
Prevalence findings for BMS have varied widely from 0.7% up to 15% of the popu-
lation depending on the diagnostic criteria [1, 6]. It has a higher predisposition in
females in the fifth to sixth decades of life, with female to male ratio reported at
1:5–1:7 [2, 4, 7]. BMS is rare in patients under 30 and appears to occur infrequently
in children and adolescents [1].
BMS is often idiopathic; however, local and systemic factors have been described
to be associated with it. Local factors can produce burning via direct irritation of the
oral mucosa; these may include dental disease, mechanical or chemical irritation,
hypersensitivity reaction, viral or bacterial infection, dry mouth, and oral lesions
[2, 8, 9]. Systemic factors include deficiency in vitamin B12, folic acid, iron, and
zinc; endocrine disorders such as diabetes; hyposalivation associated with autoim-
mune disease such as Sjögren’s syndrome; medications including angiotensin
20 Burning Mouth Syndrome 225
-converting enzyme inhibitors (ACEI), benzodiazepines, neuroleptics, antihista-

mines, and antiretroviral; and taste disorders and reflux disease [2, 10]. Psychological
stress and neuropathy have also been suggested [2].
20.3.1 Burning Symptoms
Burning varies from patient to patient in intensity and location. It can occur in one or
multiple locations within the oral cavity and commonly affects the dorsal tongue, pal-
ate, lips, and gingival tissue and is often bilateral but can also occur unilaterally [10].
The onset of pain is often spontaneous and can be described by patients as burning,
tingling, annoying, tender, or numb and is often constant [1]. Pain intensity varies
throughout the day from no pain or mild pain in the morning to moderate to severe
pain by late afternoon with the greatest intensity by late evening [6]. Oral stimulation
with food or gum and mints often decreases the pain in these patients [10].
20.3.2 Associated Symptoms
The burning sensation is often associated with alteration in taste often reported as
bitter, metallic, or sour and with xerostomia or a sensation of oral dryness in approx-
imately two-thirds of patients [1, 10]. Salivary flow studies have demonstrated nor-
mal stimulated salivary flow with reduction in resting salivary flow in BMS as well
as alterations in the composition of saliva [11–14]. Taste thresholds in BMS have
been found to be elevated leading to decreased sensitivity to taste stimuli [15]. Other
associated symptoms may include thirst, headache, and temporomandibular joint
pain or tenderness [3].
20.3.2.1 Psychosocial
In some cases of BMS, the severe chronic pain can be associated with major depres-
sive disorder, generalized anxiety disorder, hypochondria, cancerphobia, decreased
openness, and higher neuroticism [12, 16]. The psychological stress experienced by
the patients may lead to poor sleep and decreased quality of life and even to suicidal
tendencies [17, 18].
Although various theories have been described, it is likely that BMS is not the result
of a single process. Rather, it is likely that a combination of processes exist in pro-
ducing the oral burning. Some of the possible processes are described below.
20.4.1 Chorda Tympani Damage
The chorda tympani, which provides taste to the anterior two-thirds of the tongue,
has been suggested to be involved in the pathogenesis of BMS. Unilateral chorda
tympani damage has been shown to produce altered taste sensation of metallic, bit-
ter, salty, and sore quality, similar to the complaints of BMS patients [19]. It has also
been demonstrated that unilateral damage to the chorda tympani can produce
increased burning in response to capsaicin contralateral to the side of the damage, a
response mediated by the trigeminal nerve [20]. Application of sweet stimuli has
also been demonstrated to inhibit oral burning, suggesting that a central loss of
inhibition on the trigeminal system from the chorda tympani can lead to oral burn-
ing [20]; this finding has been supported by a recent MRI study of the gray matter
in both BMS and dysgeusic patients which showed evidence of similarity in the
regions affected [21].
20.4.2 Small Fiber Neuropathy
Small fiber neuropathy has been demonstrated with a significant reduction of small
fiber density in areas of burning in BMS [22, 23], which has been suggested to relate
to changes in immune system function.
It has been noted that burning can be a complaint in autoimmune diseases such
as Sjögren’s syndrome and oral lichen planus and can also occur as a result of a
delayed contact sensitivity reaction [8], suggesting the possibility of a humoral
response producing antibody against nerve tissue antigens, leading to small fiber
neuropathy [24]. It has also been suggested that nerve growth factor (NGF), found
to be elevated in saliva of BMS patients, may interact with mast cells and cause
release of inflammatory mediators, which may result in the destruction of small
nerve fibers in the oral mucosa [25]. NGF also upregulates expression of transient
receptor potential vanilloid channel type 1 (TRPV-1) in tongue papillae and volt-
age-gated sodium channels 1 and 8 (Nav 1, 8) in tongue subepithelium; two ion
channels associated with nociception in BMS [22, 23, 26], suggesting increased
nociceptive activity in the remaining small diameter nerve fiber may contribute to
the burning.
20.4.3 Other Theories
Burning pain related to central dopamine deficiency has also been proposed as an
etiological factor in BMS in view of the similarities between the BMS and
Parkinson patients on nerve conduction tests and the successful treatment of oral
burning in some patients with levodopa [27]. Additional support for this mecha-
nism is the demonstration on positron emission tomography (PET) of a reduction
in dopamine in the nigrostriatal neurons and the putamen in the basal ganglion
[5]. Other suggested pathogenesis includes hormone alterations associated with
stress response and menopause and subclinical trigeminal neuralgia [5, 14, 28].
Burning mouth pain has remained a diagnosis of exclusion despite recent advances
in our knowledge of this syndrome and despite awareness of alterations in periph-
eral and central neural tissues as well as disturbances of taste. Although various
classification systems outline different presentation of BMS, they are not especially
helpful in determining management or long-term progress (Table 20.1).
Table 20.1 Diagnostic aids for burning pain

Patient complaints
1. Pain quality: burning, constant, mild in the morning, and increase during the day
2. Associated symptoms: dry mouth, metallic taste, sour taste
3. Often have some relief with drinking water, eating, sucking on gum/candy
Physical examination
Examination should include the tongue, buccal mucosa, lips, gingiva, and dentition
Look for striae, vesicles, trauma, and dental erosion to rule out other conditions such as
Candida infection, lichen planus, herpes, Sjögren’s syndrome, head and neck radiation, etc.
Salivary flow [11]
Low unstimulated flow, normal stimulated flow often seen in BMS
Normal unstimulated >1.5 ml/5 min
Normal stimulated >4.5 ml/5 min
Blood tests are done to rule out systemic causes of burning
CBC, ESR, Zinc, B12, folate, ferritin, glucose
Autoimmune panel: Rh, ANA Anti-Ro (SSA), Anti-La (SSB)
Serum hormones
Spatial taste testing [19]
Superthreshold taste solutions [sweet (1 M sucrose), sour (0.032 M citric acid), bitter
(0.001 M quinine hydrochloride), and salty (1 M NaCl)] and 50% ethanol (produces pain)
There is often taste deficit in areas of burning
Other studies [1, 3]
Generally, a diagnosis of BMS can be made with a good clinical examination and history;
however, other diagnostic test can be performed to exclude other disorders as cause of the
burning
Neurological imaging to rule out pathology and degenerative disorder
Patch test to look for presence of allergy
GI assessment to look for reflux
Oral culture to rule out infections include bacterial, viral, and fungal
Table 20.2 Scala et al. Fundamental 1. Daily bilateral or unilateral burning of oral mucosa
(2003) diagnostic criteria 2. Pain for at least 4–6 months
criteria of BMS [3] 3. Constant and progressively increasing intensity
throughout the day
4. Symptoms improves with eating food or liquid
5. Pain does not interfere with sleep
Additional 6. Associated symptoms: dysgeusia, xerostomia
criteria 7. Chemosensory changes
8. Mood disorders
Diagnosis remains complex since patients treated successfully for the physical
oral changes may not necessarily improve, suggesting that neural changes may have
also occurred as a result of the initial insult including the possibility of changes to
taste system which is slow to recover.
Previous studies have shown that even a condition such as geographic tongue
which causes transient changes in the architecture of the tongue, including both the
filiform and fungiform papillae, can lead to higher risk of developing burning
mouth pain [9].
With the possibility that BMS is linked to changes in taste, in addition to other
blood tests, determining serum zinc level may also be helpful since zinc has been
linked to taste loss, and Cao et al. (2010) have demonstrated that zinc supplementa-
tion may be helpful for BMS [29]. Medications which can cause change in taste [30]
may be related not only to alteration in taste but also to burning mouth pain second-
ary to taste changes.
Examination should also include determination of salivary flow rates for evi-
dence of decreased unstimulated salivary flows in the presence of normal stimulated
salivary flow [11]. Spatial taste test for deficits in fungiform and circumvallate
papillae innervated by the chorda tympani and glossopharyngeal nerve is helpful in
determine taste deficit in BMS [19]. Trigeminal testing may also be helpful in deter-
mining the sensitivity of the trigeminal system to pain, which may also be a sign of
release of inhibition [20].
Rarely, imaging studies may be helpful. However, even with this information, a
specific etiological factor for BMS often remains unclear and approach to diagnosis
and treatment continues to be by trial and error. See Table 20.2 for proposed diag-
nosis criteria for BMS [3].
In view of the belief that BMS is likely a neuropathic pain, either with no clinical
findings or clinical findings which have been successfully addressed without remis-
sion of pain, current treatment is directed mostly at pain control and symptom
reduction [5]. Medications such as clonazepam (a benzodiazepine), pregabalin, or
gabapentin (GABA analogues) are commonly prescribed for BMS because of their
ability to enhance inhibitory effect on neurons. Tricyclic antidepressants, such as
amitriptyline, which has been used for the treatment of neuropathic pain [31], have
also been used in the treatment of BMS. Low-dose benzodiazepine and tricyclic
antidepressants are usually too low to affect depression or anxiety and are more
likely related to their impact on pain [32], rather than depression or anxiety.
Treatment of an underlying cause in secondary BMS may sometimes, but not

always, alleviate the symptoms of burning pain with residual symptom treated in the
same way as primary BMS. Listed below are some agents that have been trialed in
the treatment of idiopathic BMS with varying results for most medications, other
than clonazepam which has been shown in multiple studies to have a good effect on
relief of symptoms in BMS [33, 34].
20.7.1 Topical Treatment
Topical treatment is aimed at symptom control to reduce the burning pain. Suggested
topical treatments include:
• Sucking on 1 mg tablet of clonazepam three times per day for 14 days [1].
• 0.15% benzydamine hydrochloride three times per day [1, 3].
• Local anesthetics such as lidocaine; however, the short duration of activity has
rendered them ineffective in pain control [1].
• Salivary substitutes [3].
• Topical antifungals [3].
• Topical aloe vera 0.5 mL gel 70% three times a day together with a tongue pro-
tector have been suggested in burning associated with parafunctional activity [1].
• Topical capsaicin (0.025% cream) or rinsing with Tabasco sauce and water (1:2
solution) or hot pepper and water (1:1 solution), although some patient may not
be able to tolerate the burning of capsaicin initially [1, 34].
20.7.2 Systemic Treatment
Suggested systemic treatments includes:
• Alpha lipoic acid (ALA) 600 mg/d for 2 months. [1, 34].

• Antipsychotics: amisulpride, levosulpiride, 50 mg/d for 24 weeks [1].
• Antihistamines [3].
• Capsaicin (systemic) 0.25% capsule, three times a day for 1 month may cause
gastric pain [1, 34].
• Clonazepam 0.5 mg/d before bed [32, 34].
• Gabapentin 100–300 mg up to three times per day.
• Hormone replacement therapy: premarin (conjugated estrogen) 0.625 mg/d for

21 days and Farlutal (medroxyprogesterone acetate) 10 mg/d from day 12–21 for
three cycles in peri- and postmenopausal women [1].
• Pregabalin 25–75 mg up to three times per day.
• Serotonin reuptake inhibitor (SSRIs): sertraline 50 mg/d, paroxetine 20 mg/d for
8 weeks, duloxetine 30–60 mg/d. Dual action serotonin-norepinephrine reuptake
inhibitor (SNRIs) appears to have better results [1].
• Supplements in those with abnormal levels on blood tests; B complex, vitamin
B12, folic acid, iron, and zinc [1].
• Zinc gluconate 140 mg daily [35].
• Tricyclic antidepressant (TCA) 5–10 mg/d and gradually increase to 50 mg/d,
although these medication must be used with care in elderly patients due to
adverse effects including sedation, anticholinergic effects, hypotension, etc. [1].
20.7.3 Complementary and Alternative Medicine Therapies
There has been some suggestion that natural remedies may offer some pain relief
but there is little evidence of its efficacy. Hypericum perforatum for mild to moder-
ate depression, anxiety, and pain has not shown improvement in BMS [34]. Catuama,
an herbal product of Brazilian origin, has been shown to have antinociceptive, anti-
depressant, and vasorelaxing properties and was reported to be effective in reducing
the burning in one double-blind clinical trial [34].
Acupuncture in BMS has been studied, although only within China. Despite
positive reported results, its efficacy is questionable [34].
20.7.4 Cognitive Therapy
Cognitive therapy, alone or in combination, has been reported to provide significant

improvement in some BMS patients [1]. The latest Cochrane review (2005) sug-
gests the best evidence for alpha lipoic acid, clonazepam, and cognitive behavior
therapy in symptom reduction in BMS [36].
20.8 Treatment Goal and Sequencing of Care
Ultimately, the goal of BMS treatment is to reduce burning and associated symp-
toms in patients with the aim of complete resolution of these symptoms. Other
important BMS management considerations to make:
• Clinical history and clinical examination are often the key to diagnosis of BMS,
in patient with a history of oral burning or oral pain, metallic/bitter taste, or dry
mouth in the presence of adequate saliva. If clinical examination or lab work
does show changes or a cause of the burning, initial treatment can address the
underlying cause. If the burning persists, then treatment should be then aimed at
symptom control secondarily to the “usual” treatment for BMS.
• Patients should be followed after several weeks after the initial consultation to
determine the impact of treatment and then followed over the next year for reas-
sessment and treatment modification if needed.
• Without treatment, approximately 28% of patients will show moderate improve-
ment, approximately half will have change to their symptoms, and approximately
19% will have worsening in symptoms [3]. It has been suggested in some study
the spontaneous remission of BMS rarely occurs [3], so that it is especially
important that patient receive excellent clinical care.
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Part VIII
Headaches
Chronic Daily Headache
21
Roger K . Cady and Kathleen Farmer
Pearls of Wisdom
• Chronic daily headache (CDH) is a descriptive term encompassing many
different headache conditions.
• It is easier to prevent CDH than to treat it. Prevention includes:
–– Establish a clear diagnosis early in the natural history of the headache
pattern.
–– Set measurable goals of treatment and outcome.
–– Provide limits for acute medication usage.
–– Start preventive medications earlier rather than later.
–– Encourage patients to participate as partners in their headache care.
–– Follow the patient’s progress over time.
• In evaluating patients with CDH, look for various mechanisms that may be
involved in driving the headache process.
• Address the patient with an interdisciplinary comprehensive approach
rather than a linear approach when appropriate.
• Non-pharmacological interventions are the foundation of treatment, not an
afterthought when the patient is not compliant with medications.
• Most CDH patients have a good prognosis and are rewarding to treat.
R.K. Cady, MD (*)

Director, Headache Care Center, Springfield, MO, USA
e-mail: rcady@banyangroupinc.com
K. Farmer, PsyD
Headache Care Center, Springfield, MO, USA

DOI 10.1007/978-3-319-51508-3_21
236 R.K. Cady and K. Farmer
21.1 Introduction
Chronic daily headache (CDH) is a diagnostic umbrella that includes many different
and often divergent headache diagnoses. Generally, it implies that a person is expe-
riencing headache on more days than not over a specified time period. CDH includes
both primary and secondary headaches, and effort should be made to establish a
more specific diagnosis whenever possible.
The current classification of the International Headache Society (IHS) first divides
headaches and facial pain disorders into primary and secondary. This differentiation
is based on whether or not headaches or facial pain is the result of underlying
pathology:
• Common primary headaches include migraine, tension-type headache, cluster

headaches, and trigeminal autonomic cephalalgias.
• Secondary headache can result from numerous underlying diseases such as
infection, tumor, medication, and trauma.
21.2.1 Primary Headaches
For migraine and tension-type headache, the diagnosis of chronic is based on a fre-
quency of 15 days of headache per month for at least three consecutive months. For
cluster headache the assignment of episodic and chronic is based on the duration of
a cluster period. When the cluster period lasts more than 1 year without remission
more than 1 month, the diagnosis of chronic cluster can be made.
21.2.1.1 Migraine
Migraine is first classified based on the presence or absence of aura into migraine
with aura and migraine without aura. An occurrence of two or more auras in a life-
time associated with a headache fulfilling criteria for migraine constitutes the diag-
nosis of migraine with aura. Aura may occur in as many as 25% of migraine attacks.
Many patients experience both migraine with and without aura over their lifetime.
The second division of migraine is based on frequency and is the basis for the
diagnosis of episodic and chronic migraine. Episodic migraine is diagnosed when
there is less than 15 days of headache per month and constitutes those attacks of
migraine with or without aura (see Table 21.1). Attacks not fulfilling these criteria
should be another diagnosis. Chronic migraine is diagnosed when there are 15 or
greater days with primary headache and eight or more fulfill criteria for migraine or
are treated early with migraine-specific medication for a headache believed would
be migraine if treated later in its course. Migraine headaches and migraine variants
are discussed in detail on Chaps. 22 and 24, respectively.
21 Chronic Daily Headache 237
Table 21.1 Comparison of clinical characteristics between migraine, tension-type headache, and
cluster headache
Chronic migraine Tension-type headache Cluster headache
Frequency: 15 days or more/ Frequency: 30 min to 7 days Frequency: more than 1 year w/o
month for more than Pain features (2 of 4): remission or with remission
3 months Bilateral lasting less than 1 month
Pain features (2 of 4): Pressing/tightening Pain features:
Unilateral location Mild to moderate Severe or very severe unilateral
Pulsating quality Not aggravated by orbital
Moderate or severe pain activity Supraorbital and/or temporal
intensity In addition: pain lasting
Aggravation by or causing No nausea 15–180 min if untreated
avoidance of routine Photophobia or Pain (1 of 6)
physical activity phonophobia Ipsilateral conjunctival
In addition (1 of 2) injection and/or
Nausea and/or vomiting lacrimation
Photophobia and Ipsilateral nasal congestion
phonophobia and/or rhinorrhea
Ipsilateral eyelid edema
Ipsilateral forehead and facial
sweating
Ipsilateral miosis and/or ptosis
A sense of restlessness or
agitation. Attacks from one
every other day to 8 per day
21.2.1.2 Tension-Type Headache

Episodic tension-type headache is diagnosed when there are less than 15 days of
headache that is mild to moderate in intensity but otherwise lacking migraine fea-
tures. Chronic tension-type headache is when there are greater than 15 days of mild
to moderate headache. A single associated feature of nausea, photophobia, or pho-
nophobia can be present.
21.2.1.3 Cluster Headache

Cluster headache is a short duration (<3 h) unilateral severe headache associated
with autonomic features on the ipsilateral side as the headache such as lacrimation,
rhinorrhea, nasal stuffiness, sweating, or miosis with or without ptosis. Cluster
attacks occur up to several times a day. It is episodic if the cluster period in less than
1 year and chronic if it persists beyond a year without greater than a month of clus-
ter free time. These are discussed in more detail on Chap. 23.
21.2.1.4 Trigeminal Autonomic Cephalalgias

Other short duration headaches occur but are rare and are differentiated from cluster
based primarily on frequency of attacks. These fall into the broad category of auto-
nomic trigeminal cephalalgias. A variety of other uncommon primary headaches
such as hypnic headache, chronic hemicrania continua, and chronic paroxysmal
hemicranias have also been defined. These are discussed in detail on Chap. 23.
21.2.2 Secondary Headaches
Secondary headaches are the consequence of an underlying disease or pathology.

Ideally when the underlying disease resolves, the headache resolves. Etiologies are
varied and may include infections, trauma, neoplasm, inflammatory disease, medi-
cation, toxic exposures, vascular disease, and psychological disease.
Worldwide, it has been estimated that prevalence among adults with headache dis-
order (defined as headache that is symptomatic at least once within the last year) is
about 50%. Up to three quarters of adults aged 18–65 years in the world have had
headache in the last year. Chronic headache (15 or more days every month) affects
1.7–4% of the adult population globally. Despite country-to-country or regional
variations, headache disorders are a worldwide concern, affecting people of all ages,
races, income levels, and geographical areas.
The long-term effort of coping with a chronic headache disorder may also predis-
pose the individual to other illnesses. For example, anxiety and depression are signifi-
cantly more common in people with chronic migraine than in healthy individuals.
Chronic migraine is more common in women, usually by a factor of about 2:1,
because of hormonal influences. This type of headache may be related to the activa-
tion of a mechanism deep in the brain that leads to release of pain-producing inflam-
matory substances around the nerves and blood vessels of the head.
Chronic tension-type headache (CTTH) affects 1–3% of adults. It often begins
during the teenage years, with a female gender to male ratio of 3:2. Etiological fac-
tors of CTTH may be stress-related or associated with musculoskeletal conditions.
The convergence hypothesis [1] was proposed as a clinical model of headache patho-
physiology and suggests that most primary headache disorders arise from a common
pathophysiological process. Underpinning this model is that migraine is a process that
evolves through multiple phases: prodrome (premonitory), aura, mild, moderate, and
severe headache, and postdrome. Not all headaches evolve through all these phases,
and this headache process can, under appropriate circumstances, be terminated at any
stage in its evolution. Symptoms observed during each of these phases provide the
overall observed symptomatology expressed by patients during a primary headache,
but only a small subset is actually used in formal diagnostic criteria (Fig. 21.1).
The convergence model predicts multiple clinical expressions of primary head-
ache disorders based on neurological disruption of the central nervous system,
peripheral sensitization, central sensitization, and the various sensory inputs into the
trigeminal nucleus caudalis and assists in understanding the relationship of cervical,
sinus, and temporomandibular factors involved in headache.
Physiological
phase of
migraine
Central
sensitization
Neurovascular
activation
Trigeminal
disinhibition
Electrical
disinhibition
Neurochemical
disruption 1 2 3 4 5
Headache diagnosis Premonitory Aura w/o Mild HA Migrainous Migraine
if Process terminates
at Different stages headache (Tension-type) headache
Pre-headache Headache
phase phase
Migraine evolution Time (hours)
Fig. 21.1 Physiological phases of migraine headache
Over time the frequency of primary headaches can increase, eventually becom-
ing chronic. Many factors can cause transformation of episodic to CDH including
head injury, infections such as meningitis, overuse of pain medication, ineffective
acute treatment, allergies, asthma, hypothyroidism, and hypertension. As the patient
evolves toward a chronic headache pattern, numerous comorbidities are observed
such as sleep disruption, affective disease, gastrointestinal symptoms, and myofas-
cial pain [2]. In addition, with the evolution of chronic headache, there is frequently
an observed overreliance on symptomatic medications. The overuse of acute symp-
tomatic medication is considered an etiological factor in many chronic headache
patients [3].
Risk factors for CDH include genetic factors, trauma (both psychological and
physical), physiological factors such as age and hormonal status, obesity, caffeine,
medications, and snoring [4]. Recently, it has been observed that patients with sub-
optimal response to acute medication are also at significant risk of developing
chronic migraine [5].
21.5.1 Diagnosing the Headache Patient
Arguably the most important element of obtaining an accurate headache diagnosis

is to establish rapport with the patient. This is best accomplished by beginning the
interview with open-ended questions that allow patients to “tell their story.”
Important areas to define during a headache history include the “5 Ps”: pattern,
phenotype, patient (comorbidities), pharmacology (all medication usage and its
effectiveness), and precipitants [6].
21.5.2 Diagnostic Criteria/Taxonomy
In 1988, the International Headache Society (IHS) established an elaborate taxon-

omy for the diagnosis of headache and facial pain disorders [7]. This was revised in
2004 and again in 2013 [8]. In the revised edition chronic migraine was recognized
for the first time, and thus the taxonomy becomes consistent in defining a chronic
form of migraine, tension-type, and cluster headache. These criteria are listed in
Table 21.1. Criteria for cervicogenic headache, posttraumatic headache, neuralgias,
sinusitis, and temporomandibular disorders and trigeminal autonomic cephalalgias
(TAC) have been also defined. For more detailed description, see Chaps. 14 and 15
for TMD, Chap. 19 for neuralgias, Chap. 22 for migraine, Chap. 23 for cluster head-
aches and TAC, and Chap. 24 for migraine variants.
In clinical reality, primary chronic headache often appears as a complex
blending of several diagnostic groupings of the IHS taxonomy. For example,
most patients with chronic migraine have some headaches that diagnostically
appear to be tension headache. Additionally, most patients with IHS migraine
believe they have multiple types of headache [9] most commonly migraine, ten-
sion, and sinus, and indeed multiple studies support the idea that patients experi-
ence headaches with a wide array of vascular, muscular, and nasal/autonomic
symptomatology [10]. This is particularly apparent as headache patterns become
more chronic.
Evaluation of the patient with CDH requires a holistic approach and a willingness
on the part of the medical provider to work as a partner with the patient. It also often
requires providers to depart from a linear cause and effect model of disease to a
model where multiple factors influence the etiology, outcome, and treatment.
Conceptually, an individual patient may have multiple factors influencing their
chronic headache, and each component needs to be dissected out, evaluated, and
treated. For example, a patient with a traumatic injury to the cervical spine may
quickly evolve into a daily headache pattern. However years of unresolved pain can
be complicated by depression, disability, and medication overuse. Without address-
ing the complexity of all factors involved, the treatment outcome of such a patient
is compromised. Consequently, many patients with CDH are best treated in interdis-
ciplinary treatment models.
Most patients seeking medical care with chronic daily headache patterns
require significant education, behavioral modification, a treatment plan that
includes pharmacological and non-pharmacological approaches, and long-term
follow-up and follow through. Common complicating factors to chronic daily
headache include:
• Comorbid conditions including sinus disorders, temporomandibular disorders,

and cervical injury
• Depression and anxiety

• Disability
• Inactivity and lack of exercise
• Medication overuse
• Dietary triggers including caffeine
• Oral parafunctional habits
• Postural habits
Treatment needs to be directed at the underlying pain mechanisms whenever pos-

sible. The following treatment options should be considered:
1. Education that focuses on engaging the patient as a partner in management is

critical to success. Each treatment plan should include behavioral therapies and
lifestyle modification such as:
• Exercise to improve posture, relaxation, and conditioning
• Relaxation to reduce reaction to stressors and relax musculature
• Positive self-talk to improve compliance and motivation for lifestyle
modification
• Regular healthy meals to reduce low glucose and other diet triggers
• Oral habit reversal such as reduced clenching and bruxism
• Caffeine reduction should be considered if a problem
• The use of diary records to track medication use, triggering events or factors,
compliance, and goals
2. Employing a treatment team is essential in more complicated cases. Members of
an interdisciplinary team may often include:
• Physician for medication management
• Psychologist for implementing a cognitive behavioral program
• Dentist to address masticatory dysfunction and temporomandibular disorders
• Physical therapist to implement an exercise and postural program
• Massage therapist to address muscular trigger points and relax muscles
• Other medical or dental specialists to address specific patient needs
3. Pharmacologically, the emphasis is on prophylaxis rather than acute abortive inter-
ventions. However, this is not to imply that acute interventions are unnecessary or
unimportant. A list of medications used for primary headaches is displayed in
(Table 21.2). The choice of prophylactic medication is based largely on the pres-
ence of comorbid disorders and avoidance of adverse reactions. For example:
• Patients with depression and terminal sleep disturbance may do best with a tricy-
clic antidepressant such as amitriptyline, 50 mg, or nortriptyline, 50 mg QHS.
• Patients with mood swings may improve with a neuromodulator such as topi-
ramate (100–200 mg/day), valproate sodium (800–1,500 mg/day), or gaba-
pentin (1,000–2,500 mg per day).
• Patients with obesity or concern about weight gain should avoid steroids and
certain antidepressant medications.
Table 21.2 List of medications used for migraine, chronic daily headache, and migraine variants,
variants
Anticonvulsants
Gabapentin (Neurontin)
Divalproex (Depakote)
Topiramate (Topamax)a
Valproate sodium (Depacon)a
Zonisamide (Zonegran)a
Triptans
Almotriptan (Axert)
Eletriptan (Relpax)
Frovatriptan (Frova)
Naratriptan (Amerge)
Rizatriptan (Maxalt, Maxalt-MLT)
Sumatriptan (Imitrex)
Zolmitriptan (Zomig, Zomig-ZMT)
Combination drugs
Acetaminophen/aspirin/caffeine (Excedrin Migraine, Excedrin Extra Strength tablets, capsules)
Acetaminophen/caffeine/butalbital
Aspirin/caffeine/butalbital (Fiorinal)
Dichloralphenazone/acetaminophen/ isometheptene (Duradin, Midrin, Migratine)
Ergotamine/caffeine
Other classes
Tricyclics such as Amitriptyline (Elavil, Endep)a
Aspirin
OnabotulinumtoxinA (Botox)
RimabotulinumtoxinB (Myobloc)a
Candesartan (Atacand)a
Coenzyme Q10a
Dihydroergotamine (DHE 45)
Ibuprofen (Advil Migraine, Motrin Migraine)
Naproxen sodium
Propranolol (Inderal)
Riboflavina
Timolol (Blockadren)
Tizanidine (Zanaflex)a
Unlabeled use
a
• Patients with morning sedation should avoid amitriptyline or other sedating

tricyclics.
4. The need for acute therapy to quickly improve the condition is often paramount
in the patient’s mind, and it is essential to address directly. To do so, a clinician
needs to take into consideration the following:
• Overuse of analgesic and acute symptomatic medication as an etiological
component of the headache pattern. Though somewhat controversial preven-
tative medication may be started before discontinuing the offending acute
medication but not in place of stopping it.
• When acute medication is prescribed, it is important to regularly assess its

effectiveness and consistency over time. Providing appropriate formulations
of abortive medications is also critical given the likelihood of GI impairment
associated with chronic headache disorders.
• Prescribing acute therapy from a different pharmacological class is often nec-
essary to disrupt the pharmacologically maintained headache cycle. For
example, use bridge therapy to protect the patient through the period of anal-
gesic withdrawal. Though not FDA approved for this indication, commonly
used treatments include repeated doses of dihydroergotamine (DHE,
0.5–1 mg/dose IV, IM, SC, or intranasal), a rapid tapering schedule of dexa-
methasone (12 mg; 8 mg; 4 mg on successive mornings or a Depo Medrol
Dosepak), or several consecutive days of a long-acting triptan such as narat-
riptan (1–2.5 mg/dose po) or frovatriptan (1–2.5 mg/dose po).
• Patients need to be followed regularly and given access to medical advice and
prescription refills in order to avoid visits to the emergency departments or
unscheduled visits to other providers during this time.
• Use of procedures such as occipital nerve blocks, trigger point injections, or
sphenopalatine nerve blocks can also be useful for selected patients.
• OnabotulinumtoxinA can be used in chronic migraine and possibly chronic
posttraumatic migraine when the headache has a migraine phenotype.
The goal of treatment is to manage headache, not to cure it. It is important to define
the specific goals and timetable with the patient. The following are important con-
siderations in headache management:
• The most common primary management goals include preserve and restore
function and establish a treatable episodic headache pattern.
• Tailor the goals whenever possible to ensure that patients participate in their
implementation.
• Establishing a timetable to accomplish the goals in stages so that they are obtain-
able is essential. For example, reduce headaches to a mild headache a few times
per week over the next 3 months.
• Patients with CDH often have long established histories of treatment failure.
Typically, they have been managed in a linear treatment model where one thing
is tried and observed over time to assess what the next step will be.
• Diagnostic workup should be completed quickly so that the therapeutic issues
can be addressed without underlying fear that problems are being overlooked.
• Engage the patient in an interdisciplinary model where multiple facets of their
headache are addressed simultaneously.
• Include daily behavioral changes for triggering or complicating factors.
• Maintain diaries with written goals that can be assessed regularly to motivate patients.
• With time, the prognosis for most patients is reasonably good.
References
1. Cady R, Schreiber C, Farmer K, Sheftell F. Primary headaches: a convergence hypothesis.
Headache. 2002;42:204–16.
2. Cady RK, Schreiber CP, Farmer KU. Understanding the migraine patient: the evolu-
tion from episodic headache to chronic neurological disease. Headache J Head Face Pain.
2004;44:426–35.
3. Bigal ME, Rapoport AM, Sheftell FD, Tepper SJ, Lipton RB. Transformed migraine and medi-
cation overuse in a tertiary headache centre clinical characteristics and treatment outcomes.
Cephalalgia. 2004;24(6):483–90.
4. Scher AI, Stewart WF, Ricci JA, Lipton RB. Factors associated with the onset and remission
of chronic daily headache in a population-based study. Pain. 2003;106:81–9.
5. Lipton RB, Fanning KM, Serrano D, Reed ML, Cady R, Buse DC. Ineffective acute treatment of
episodic migraine is associated with new-onset chronic migraine. Neurology. 2015;84:688–95.
6. Cady RK, Lipton RB, Rothrock JF. Chronic migraine: a patient-centered guide to effective
management. Hamilton: Baxter Publishing; 2013.
7. International headache Society. Classification and diagnostic criteria for headache disorders,
cranial neuralgias and facial pain. Cephalalgia. 1988;8(Suppl 7):1–96.
8. Headache Classification Subcommittee of the International Headache Society. The interna-
tional classification of headache disorders. 2nd edition. Cephalalgia. 2004;24(suppl 1):1–160.
9. Diamond ML. The role of concomitant headache types and non-headache co-morbidities in
the underdiagnosis of migraine. Neurology. 2002;58:S3–9.
10. Schreiber CP, Hutchinson S, Webster C, et al. Prevalence of migraine in patients with a history of
self-reported or physician-diagnosed “sinus” headache. Arch Intern Med. 2004;164:1769–72.
Migraine
22
Steven B. Graff-Radford†
Pearls of Wisdom
• Migraine is typically a very disabling primary headache disorder that
unfortunately remains underdiagnosed and untreated.
• There is no cure for migraine; nevertheless there are numerous interven-
tions that may help restore an improve life for sufferers. These measures
should consider the patient in as broad an aspect as possible.
• Triggering factors, neurogenic inflammation, vascular changes, and pain
transmission should all be addressed aggressively.
• Individualizing treatment and use of multiple modalities is essential.
Migraine is one of the most common primary headache disorders with high levels
of personal disability [1, 2]. It may be very disabling secondary to the pain and
associated symptoms including nausea, vomiting, visual aura, and photo- and pho-
nophobia. Missed work and lost productivity secondary to migraine create a signifi-
cant public burden at great cost. Nevertheless, migraine still remains largely
undertreated and underdiagnosed [3]. Less than half the sufferers are diagnosed by
their physicians. Migraine must be differentiated from secondary headache disor-
ders. The International Headache Society has put forward specific criteria for
headache classification in 1988 [4]. These are currently being revised in a 3rd edi-
tion (Beta version) [5].” Please keep the reference intact.
†Author was deceased at the time of publication.

S.B. Graff-Radford, DDS
The Pain Center, UCLA School of Dentistry, Los Angeles, CA, USA
e-mail: denjnarf@nus.edu.sg
DOI 10.1007/978-3-319-51508-3_22
246 S.B. Graff-Radford
Table 22.1 Migraine 1. Migraine without aura

headache subcategories 2. Migraine with aura
3. Childhood periodic syndromes that are commonly precursors
of migraine
3.1. Cyclical vomiting
3.2. Abdominal migraine
3.3. Benign paroxysmal vertigo of childhood
4. Retinal migraine
5. Complications of migraine
5.1. Chronic migraine
5.2 Status migrainosus
5.3. Persistent aura without infarction
5.4. Migraine infarction
5.5. Migraine-triggered seizure
6. Probable migraine
Part I: The primary headaches.

Part II: The secondary headaches.
Part III: Cranial neuralgias, central and primary facial pain, and other headaches.
Despite the fact that all pain in the head and face is conducted by the trigeminal
nerve, the classification allows for clinical symptoms to be subclassified. This
enables each classified entity to be studied, helping determine the pathophysiol-
ogy and ultimately the treatment.
The subcategories of migraine are listed in Table 22.1.
Migraine may be very disabling secondary to the pain and associated symptoms
including:
• Throbbing headache
• Unilateral location
• Moderate to severe in intensity
• Aggravated by routine physical activity
• Nausea and vomiting
• Photophobia and phonophobia
Aura occurs in approximately 10% of migraine sufferers about 10% of the time.
The aura is characterized by recurrent attack of reversible focal neurological symp-
toms that develop over 5–20 min and last less than 60 min. Migraine presents itself
in four clinical stages:
22 Migraine 247
• Stage 1 – Premonitory stage. Patients during this phase complain of tiredness
and a craving for sweet or salty foods; they are more moody and don’t function
as well as normal.
• Stage 2 – Aura. Aura symptoms are described as visual disturbances such as
flashing lights (scotoma), a zigzag pattern (fortification spectra), or other visual
or sensory changes. The aura usually starts in the middle of the visual field and
progresses outward until it disappears. The aura is thought to be caused by an
electrical cortical spread described as similar to the spreading depression of
Leao. This cortical depolarization is followed by a decrease in cortical blood
flow. Aura occurs in 10–20% of migraine patients about 10% of the time.
• Stage 3 – Headache. The pain is started by a change in the brain, known as the
migraine generator. This area as seen in sophisticated imaging studies is located
in the brainstem and is likely a lack of central inhibition. It results in an inflam-
mation around the brain blood vessels and results in pain messages perceived as
throbbing headache.
• Stage 4 – Recovery. During this phase there is normalization and functional
restoration.
22.2.1 Etiology and Epidemiology
Migraine generally begins in childhood to early adulthood. While migraines can

first occur in an individual beyond the age of 50, advancing age makes other types
of headaches more likely. Evaluation for secondary headache should nevertheless
be considered if it is a new onset headache below age 5 or over age 50. According
to the Global Burden of Disease Survey 2010, migraine was ranked as the third most
prevalent disorder and seventh-highest specific cause of disability globally [6].
A family history is usually present, suggesting a genetic predisposition in
migraine sufferers. In addition to diagnosing migraine from the clinical presenta-
tion, there should be an accompanying normal examination.
Patients with the first headache ever, worst headache ever, or where there is a
significant change in headache or the presence of neurological symptoms like visual
or hearing or sensory loss may require additional tests. The tests may include blood
testing, brain scanning (either CT or MRI), and a spinal tap. Migraine occurs more
frequently in females than males. Waters’ data indicates the prevalence of migraine
as approximately 30% of women and 17% of men in the third decade, 26% vs. 16%
in the fourth decade, 17% vs. 13% in the fifth, and 10% vs. 5% after age 75 [7]. A
genetic factor or familial history is present in most migraineurs. The migraine
occurs commonly in the first four life decades, then the frequency decreases [8]. A
small group of migraineurs transforms into chronic daily headache now classified as
chronic migraine (ICHD classification 1.5). Chronic migraine requires headache
more than 15 days per month, at least eight fulfilling criteria for migraine and head-
ache should last more than 4 h.
Migraine pathophysiology is best discussed using the various clinical stages as a

guide. The migraine problem has four stages referred to as the premonitory stage,
the aura stage, and the headache and the recovery stages [9].
Stage 1 – Premonitory stage. The clinical presentation associated with alteration in
mood is attributed to changes occurring in the hypothalamus [9]. Little is known
as to how this is initiated, but it is postulated that migraine sufferers are geneti-
cally predisposed and that emotional, hormonal, or other triggering factors spark
the cascade leading to pain.
Stage 2 – Aura. The aura is associated with a brain neural depolarization beginning
in the occipital cortex and resultant spreading oligemia (reduction in cerebral
blood flow). Woods and colleagues reported changes in regional blood flow in a
migraine volunteer using a PET study [10]. This patient did not have an aura, only
transient visual disturbance, suggesting the blood flow changes occur in migraine
with and without aura. Migraine with aura may be associated with a state of neu-
ronal hyperexcitability linked to N-methyl-D-aspartate (NMDA) [11]. This
requires the presence of low magnesium levels and glutamate. It is unlikely the
headache is due to the blood flow reduction followed by reflex vasodilatation as
the pain develops while the reduction in flow is present. Most clinicians believe
the aura symptoms are due to neuronal dysfunction and not ischemia [9].
Stage 3 – Headache. Moskowitz has proposed that the pain perceived in migraine is
due to trigeminal neuronal activation surrounding cephalic blood vessels [12].
This system may be activated through (a) biomechanical modulation (hormones,
mast cell constituents, alcohol and drugs, platelet contents, foods), (b) mechani-
cal modulation (stretch), (c) ionic modulation (spreading depression), (d) neural
modulation (opiate containing fibers, sympathetic and parasympathetic), and (e)
central modulation (periaqueductal gray, special senses such as light and sound,
altered physiologic states such as sleep and stress). Serotonin and unstable sero-
tonergic neurotransmission have been implicated in the migraine hypothesis
[13]. Although there is compelling evidence for serotonin having some role, the
exact mechanism has not been identified but may involve effects on the raphe
nuclei, platelets, and other sites where serotonin receptors are present. Serotonin
agonists such as ergots and the triptans (sumatriptan, naratriptan, zolmitriptan,
rizatriptan, and eletriptan) support the serotonergic system role in migraine [9].
There needs to be an altered state of neural excitability causing a change in neu-
rochemistry and neurophysiology. Signals are sent from the “migraine genera-
tor” located in the dorsal raphae nucleus and in the dorsal pons [14]. These
signals arrive at peripheral perivascular nerve terminals causing release of vaso-
dilators and nerve sensitizing peptides, substance P, calcitonin gene-related pep-
tide (CGRP), and neurokinin A [12]. This plasma extravasation may be produced
by nitric oxide [15]. The ensuing vasodilatation and neurogenic inflammation
causes nociceptive activation of trigeminal sensory pathways (c fibers). Thus, the
pain message is relayed to the trigeminal nucleus, thalamus, and cortex. Recently
Burstein has demonstrated the understanding that the peripheral neuronal sensi-
tization can be significantly attenuated by the triptans providing they are used
22 Migraine 249
before central sensitization occurs. Clinically this sensitization is seen as an ipsi-

lateral allodynia, which can progress to an extracephalic allodynia if thalamic
sensitization occurs [16–18].
Stage 4 – Recovery. During this phase there is a renormalization of brain hyperex-
citability and functional restoration.
While diagnosis is made primarily through history and the ruling out of secondary
headache, it is suggested that if patients present with intermittent recurrent head-
ache, asking three questions about three characteristic symptoms can provide a very
high probability of making a migraine diagnosis:
1. About nausea: Are you nauseated or sick to your stomach when you have
headache?
2. About disability: Has a headache limited your activities for a day or more in the
last 3 months?
3. About photophobia: Does light bother you when you have a headache?
As a result, if two out of these three symptoms above are present, then there will
be a 93% positive predictive value; if three out of three symptoms, a 98% positive
predictive value [19].
Treatment can be acute, preemptive, or preventive. Acute treatment is initiated dur-

ing an attack to relieve pain and disability and to stop progression of the attack.
Preemptive treatment is used when a known headache trigger exists, such as exer-
cise or sexual activity, and for patients experiencing a time-limited exposure to a
trigger, such as ascent to a high altitude or menstruation. Preventive treatment is
maintained for months or even years to reduce attack frequency, severity, and dura-
tion. Patients taking preventive medication can also use acute and preemptive medi-
cation [20–22].
One of the important parts in managing patients with migraine is to help them
learn how to manage their own illness. This includes educating them about the cas-
cade of events that occurs with each attack. Understanding that early treatment will
improve response to therapy is an important component to also realizing that this
approach will lead to less medication use and less disability. Learning how to rec-
ognize migraine vs. other headache types (e.g., tension-type headache) will also
help the patient to know when to take a migraine-specific medication or other anal-
gesic. Preliminary studies have been done that assess the efficacy of giving triptans
during an aura. When given during an aura, triptans do not show consistent efficacy
in aborting or preventing the migraine. Therefore, until further studies are done, it is
also helpful to educate the patient to not take their triptan during the aura phase but
rather early in the pain phase of the attack.
22.6.1 Pharmacological Therapy
A number of medications are available to treat migraine, and choice depends on the
severity and frequency of headaches (see Table 22.2). These categories of medica-
tions include nonspecific and specific treatments:
Table 22.2 Pharmacological Acute therapies

agents used in migraine A. NSAIDs as initial therapy
management Aspirin, 325–975 mg/dose po
Ibuprofen, 400–800 mg/dose po
Naproxen sodium, 375–550 mg/dose po
Combination of acetaminophen/aspirin/caffeine, 2 tablets po
B. Migraine-specific agents when NSAIDs are ineffective
Dihydroergotamine, 0.5–1 mg/dose intranasally or
parentally
Naratriptan, 1–2.5 mg/dose po
Sumatriptan, 50–100 mg/dose po or 6 mg/dose SC
Combination sumatriptan 85 mg/naproxen sodium
500 mg po
Rizatriptan, 5–10 mg/dose po
Zolmitriptan, 2.5–5 mg/dose po
Eletriptan, 20–40 mg po
Diclofenac powder 50 mg po (dissolved in water)
Preventive therapies
Amitriptyline, 25–150 mg/daya
Nortriptyline 10–100 mg/day
Venlafaxine 37.5–150 mg/daya
Divalproex sodium, 500–1,500 mg/day
Gabapentin 500–2,000 mg/daya
Topiramate 100–200 mg/day
Propranolol, 80–240 mg/day
Timolol, 20–30 mg/day
Atenolol 25–150 mg/day
Nadolol 10–20 mg/day
Candesartan 4–16 mg/daya
Verapamil 40–240 mg/daya
Methylergonovine 0.2–1.2 mg/daya
Memantine 5–20 mg/daya
Magnesium 400 mg/daya
Riboflavin 400 mg/daya
Petadolex 50–75 mg/daya
Preventative therapy for Chronic migraine
Onabotulinum toxin (Botox) 155 units
Unlabeled use
a
22 Migraine 251
A. Nonspecific therapeutic treatments are those effective for any pain disorder and
include:
• Nonsteroidal anti-inflammatory drugs (NSAIDs)
• Combination analgesics
• Opioids
• Neuroleptics/antiemetics
• Corticosteroids
B. Specific therapeutic agents are those specifically effective for migraine and
related disorders [23] and include:
• Ergotamine-containing compounds
• DHE
• Triptans
For patients with early or significant nausea or vomiting, select a non-oral route
of administration. Use of transcutaneous and nasal spray on subcutaneous adminis-
tration may be beneficial.
22.6.1.1 Acute Therapy

Triptans, as a class, represent a significant advancement in the therapeutic manage-
ment of migraine. These agents have been described as receptor-specific agonists
toward serotonin or 5-HT receptors. Specifically, they are selective 5-HT1B/1D
agonists having the greatest affinity for these receptors. Blockade of 5-HT1 recep-
tors has been shown to result in acute migraine relief.
• Triptans, relative to nonspecific therapies, including analgesics and NSAIDs,

provide rapid onset of action (between 15 min and 1 h, depending on the formu-
lation), are highly effective in relieving migraine pain symptoms, and have a
favorable side effect profile.
• All agents in this class have proven therapeutic efficacy (see Table 22.1).
• In the majority of patients, the intensity of adverse effects is mild and of short
duration. Adverse effects can include chest pressure, flushing, dizziness, drowsi-
ness, and nausea. Patients who are at risk for coronary heart disease, diabetes,
obesity, severe uncontrolled hypertension, or hypercholesterolemia should be
screened prior to administration of triptans [9, 24].
22.6.1.2 Preventive Therapy

The major medication groups for preventive migraine treatment include anti-
convulsants, ß-adrenergic blockers and calcium channel antagonists, NSAIDs,
serotonin antagonists, and others (including riboflavin, minerals, herbs).
Preventive medications are taken whether or not headache is present in an
attempt to reduce the frequency and perhaps the severity and duration of antici-
pated attacks. Onabotulinum toxin is the only agent approved for prevention of
chronic migraine [25].
A preventive migraine drug could raise the threshold to activation of the migraine
process either centrally or peripherally. Drugs conceivably can decrease activation
of the migraine generator, enhance central antinociception, raise the threshold for
spreading depression, and stabilize the more sensitive migrainous nervous system
by changing sympathetic or serotonergic tone.
Preventive drugs most likely work by more than one mechanism. The drugs
could, in part, have a peripheral mechanism of action similar to specific acute medi-
cations [24, 26–28].
If preventive medication is indicated, the agent preferentially should be chosen
from one of the first-line categories, based on the drug’s side effect profile and the
patient’s coexistent and comorbid conditions.
• Preventative therapy should be initiated with the lowest effective dose of the
chosen pharmacologic agent.
• Increase the dose slowly until clinical benefits are achieved in the absence of
adverse events or until limited by adverse events. Give each treatment an ade-
quate trial. Avoid interfering medications (i.e., overuse of certain acute medica-
tions, such as ergotamine and caffeine).
• Monitor compliance. A clinical benefit may take as long as 2–3 months to
become apparent. Patients commonly take new treatments for 1–2 weeks without
seeing an effect and then discontinue prematurely, with both the physician and
patient believing the medication was not effective. Long-acting formulations
may improve compliance.
• Maximize compliance by discussing the following with the patient:
–– Rationale for the particular treatment.
–– When and how to use the treatment.
–– Adverse effects that may be likely.
–– Address and establish patient expectations: Discuss the expected benefits of
therapy and how long it will take to achieve them, and create a formal man-
agement plan based on patient preferences.
• Use daily diary – Monitor the patient’s headache by having them keep a user-
friendly diary to measure attack frequency, severity, duration, disability, response
to type of treatment, and adverse medication effects.
• After a period of stability, consider tapering or discontinuing treatment [24, 26, 27].
22.6.1.3 Considering Coexisting Diseases

Some comorbid conditions are more common in persons with migraine. These con-
ditions include stroke, myocardial infarction, Raynaud’s phenomenon, epilepsy,
affective disorders, and anxiety disorders. Coexisting diseases present both treat-
ment opportunities and limitations.
• Once the coexistent condition has been identified, select a pharmacologic agent
that will treat both disorders.
• Establish that the coexistent disease is not a contraindication for the selected
migraine therapies (e.g., β-blockers are contraindicated in patients with asthma).
22 Migraine 253
• Ensure that treatments being used for coexistent conditions do not exacerbate
migraine.
• Beware of interactions between pharmacologic agents used for migraine and
those used for other conditions. Special attention should be directed to women
who are pregnant or want to become pregnant. Preventive migraine medications
may have teratogenic effects. If treatment is absolutely necessary, select a treat-
ment with the lowest risk of adverse effects to the fetus [27] or select non-
pharmacologic interventions.
22.6.2 Non-pharmacological Therapy
Non-pharmacological, behavioral, and physical techniques should be emphasized

in the management of headache particularly with those occurring in pregnant
women. These methods should be considered for use with all migraine sufferers as
part of a rehabilitation team approach. Even if they are incompletely effective, they
may provide important augmentative benefits to pharmacological therapy. Strategies
that are found to be useful in migraine management include:
• Biofeedback including both temperature and electromyography control.

• Physical therapy including stretching, aerobic, and postural exercise.
• Relaxation techniques of many varieties. In one study, pregnant patients treated
with physical therapy, relaxation, and biofeedback had an 81.2% reduction in
headache compared to a 32.7% reduction in a control population. Third
party payers that generally do not provide coverage for these methods of treat-
ment will often approve exceptions for pregnant patients, in an effort to avoid
medication use.
• Trigger point injections – In women with identifiable trigger points, local anes-
thetic infiltration can be safely performed during pregnancy.
• “Avoidance therapy,” involving the identification and elimination of headache
trigger factors such as excess caffeine, lack of sleep, or skipping meals, should
also be emphasized.
• A temporary reduction in work hours or a medical leave of absence from work
may also be useful in avoiding the need for pharmacologic treatment of
headaches.
22.7.1 Goals
The goals of treatment are to:
1 . Relieve or prevent the pain and associated symptoms of migraine

2. Optimize the patient’s ability to function normally
22.7.2 Stratified Approach
With use of pharmacological agents, a stratification approach, in which definitive

successful treatment is used early in the course of the disease and early in the
evolution of each attack, as opposed to the step-care approach, in which less pow-
erful or nonselective drugs are tried first and if not working progress to more
potent agents. Not only are lower potency agents may be less efficacious in some
patients, but if they do not work, the patient often does not return to the office.
Patients with less severe migraine may obtain adequate relief from an
NSAID. Patients with moderate to severe migraine benefit from using a triptan as
a first-line agent.
22.7.3 Evaluating Therapy
It is important to give sufficient trial to the initial acute medication agent. Treat at
least two or three attacks before judging the effectiveness of the therapeutic choice.
If treatment is not working, consider the following:
• Reconsider diagnosis: Secondary headaches, although not as common, may

present with clinical signs and symptoms that resemble migraine.
• Treat early: Recent studies, both prospective and retrospective, support
improved response to triptan therapy when patients treat early in the course of
an attack. This is especially pertinent in those who are at risk of developing
cutaneous allodynia. Triptans have been shown to be less effective in patients
who develop cutaneous allodynia in association with their migraine (summa-
rized below).
• Dose and route of administration: If the patient is experiencing some relief from
the current medication, would a higher dose be more efficacious? If the patient
requires more rapid onset of pain relief, would a nasal spray or an injectable
formulation of the present medication suffice?
• Choice of drug: If a nonspecific agent, such as a combination analgesic, is being
used, would another nonspecific medication, such as an opioid, or a specific
medication, such as a triptan, be more effective?
• Adverse drug interactions: Investigate the use of interfering medications, includ-
ing other over-the-counter analgesics and medications for depression and heart
disease.
• Adjunctive therapy: Patients experiencing nausea and vomiting may benefit from
the addition of adjunctive antiemetics.
• Additionally, be sure there are no other medications that may be exacerbating or
triggering migraine (e.g., caffeine, herbal preparations, oral contraceptives,
among others) [21].
22 Migraine 255
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Cluster and Facial Headache
23
Robert G. Kaniecki
Pearls of Wisdom
• Trigeminal autonomic cephalalgias (TACs) are primary headache disor-
ders characterized by unilateral head pain of varying duration associated
with ipsilateral cranial autonomic features.
• TACs differ primarily in episode duration, frequency, and periodicity.
• Cluster headache and short-lasting unilateral neuralgiform headache with
conjunctival injection and tearing (SUNCT) are more common among
men, while chronic paroxysmal hemicrania (CPH) and hemicrania conti-
nua (HC) among women.
• The duration of headache attacks (15–180 min) helps differentiate cluster
headache from the other TACs and also from migraine headache (4–72 h).
• SUNCT is best differentiated from trigeminal neuralgia (TN) by location
of pain (V1 versus V2–V3 for TN) and the prominent ipsilateral autonomic
features (rare in TN).
• Cerebral blood flow studies reveal hyperactivation of the hypothalamus
ipsilateral to the pain in cluster headache, contralateral to the pain in CPH
and HC, and bilateral in SUNCT.
• Oxygen therapy and subcutaneous sumatriptan are the agents of choice for
the treatment of acute attacks of cluster headache.
• Prevention of cluster headache is most frequently accomplished with
short-term corticosteroids and long-term verapamil. Electrocardiographic
monitoring is necessary for those patients with cluster headache requiring
verapamil doses greater than 240 mg.
R.G. Kaniecki, MD
Department of Neurology, University of Pittsburgh, Pittsburgh, PA, USA
e-mail: kanieckirg@upmc.edu

DOI 10.1007/978-3-319-51508-3_23
258 R.G. Kaniecki
• Paroxysmal hemicrania and hemicrania continua are prevented abso-

lutely by therapeutic doses of indomethacin. Co-administration of a pro-
ton pump inhibitor may improve the tolerability of long-term indomethacin
dosing.
• SUNCT is the most brief, least common, and most refractory
TAC. Lamotrigine is the treatment of choice.
Although occasionally seen after an isolated incident, most patients with head or
facial pain will present with patterns of recurrent or chronic discomfort. The vast
majority will present with a primary headache disorder arising from a biological
disorder of the brain. Formal criteria for the diagnosis of primary and secondary
headache disorders were recently updated in the International Classification of
Headache Disorders, third edition, beta version (ICHD-3 beta). Among the four
primary headache categories, migraine headaches and tension-type headaches
are much more common than the trigeminal autonomic cephalalgias (TACs).
These conditions share in common attacks of head pain localized mainly in the
distribution of the ophthalmic branch of the trigeminal nerve accompanied by
one or more ipsilateral cranial autonomic symptoms (Tables 23.1–23.4).
Cluster headache is the most common and well-recognized form of trigemi-
nal autonomic cephalalgia. Previously known as Horton’s headache or Sluder’s
Table 23.1 ICHD-3 diagnostic criteria for cluster headache

A. At least five attacks fulfilling criteria B–D
B. Severe or very severe unilateral orbital, supraorbital, and/or temporal pain lasting
15–180 min (when untreated)
(b) Nasal congestion and/or rhinorrhea
(c) Eyelid edema
2. A sense of restlessness or agitation
D. Attack frequency from one every other day to eight per day when the disorder is active
Adapted with permission from Headache Classification Subcommittee of the International
Headache Society [7]
ICHD-3 International Classification of Headache Disorders, third edition
23 Cluster and Facial Headache 259
Table 23.2 ICHD-3 diagnostic criteria for paroxysmal hemicrania

A. At least 20 attacks fulfilling criteria B–E
B. Severe unilateral orbital, supraorbital, and/or temporal pain lasting 2–30 min
2. Nasal congestion and/or rhinorrhea
3. Eyelid edema
D. Attacks have a frequency above five per day for more than half the time
E. Attacks are prevented absolutely by therapeutic doses of indomethacin
F. Not better accounted for by another ICHD-3 diagnosis
Table 23.3 ICHD-3 diagnostic criteria for short-lasting unilateral neuralgiform headache
A. At least 20 attacks fulfilling criteria B-D
B. Moderate or severe unilateral head pain, with orbital, supraorbital, temporal, and/or
trigeminal distribution, lasting for 1–600 s and occurring as single stabs, series of stabs, or in a
sawtooth pattern
2. Nasal congestion and/or rhinorrhea
3. Eyelid edema
D. Attacks have a frequency of at least once a day for more than half of the time when the
disorder is active
neuralgia, cluster headache is characterized by unilateral short-duration attacks

of severe head pain associated with prominent ipsilateral autonomic symptoms.
Episodic cluster typically occurs in periods lasting from 1–12 weeks, separated
by pain-free periods lasting at least 1 month. When headache attacks occur for
more than 1 year without remission, or when remission periods last less than
1 month, the term chronic cluster is applied. Less common are the other trigemi-
nal autonomic cephalalgias: paroxysmal hemicranias (PH), also divided into
episodic (EPH) and chronic (CPH) forms by criteria identical to that for cluster;
short-lasting unilateral neuralgiform headache with conjunctival injection and
260 R.G. Kaniecki
Table 23.4 ICHD-3 diagnostic criteria for hemicrania continua

A. Unilateral headache fulfilling criteria B–D
B. Present for >3 months with exacerbations of moderate or greater intensity
(b) Nasal congestion and/or rhinorrhea
(c) Eyelid edema
2. A sense of restlessness or agitation or aggravation of the pain by movement
D. Responds absolutely to therapeutic doses of indomethacin
tearing (SUNCT) and the related short-lasting unilateral neuralgiform headache

with cranial autonomic features (SUNA); and hemicrania continua (HC). PH
and SUNCT/SUNA appear phenotypically similar to cluster headache but are
shorter in duration and typically recur at a higher frequency [14]. It is crucial to
distinguish among the various TAC subtypes since management strategies differ
significantly. Unlike the other TACs, hemicrania continua is characterized by
baseline constant or nearly continuous unilateral head discomfort. It was
recently reclassified as a TAC with the rationale that the pain is typically strictly
unilateral and accompanied by ipsilateral cranial autonomic symptoms [2].
The location and description of pain and variety of autonomic symptoms are similar
among the TACs [12]. The most intense area of pain typically is centered near the
temple and orbit, with occasional patients reporting facial, more widespread hemi-
cranial, or occipital radiation. The discomfort is nearly always intense and often
described as stabbing, searing, boring, or throbbing. Accompanying the pain is any
combination of the following cranial autonomic features: conjunctival injection or
lacrimation, nasal congestion or rhinorrhea, eyelid edema, forehead or facial flush-
ing or sweating, miosis, ptosis, or a sense of ear fullness. A sense of restlessness or
agitation also is frequently reported. In HC the autonomic features may only be seen
during moderate-to-severe exacerbations of the underlying chronic head pain, at
which point migraine-like symptoms may also be described. Unlike the other TACs,
hemicrania continua patients may describe aggravation of pain with physical activ-
ity. A foreign body sensation in the ipsilateral eye, similar in feeling to a grain of
sand, is not listed among the criteria for HC but is quite common.
The TACs will differ significantly in episode duration, frequency, and periodicity
[6]. Cluster may last 15–180 min and recur one to eight times daily over a span of
weeks to months. PH attacks last 2–30 min and recur up to 40 times per day, while
SUNCT/SUNA attacks last 1–600 s and may recur more than 100 times daily. Both
PH and SUNCT/SUNA possess temporal profiles extending over months to years and
sometimes decades. SUNA differs from SUNCT in that it is diagnosed when only one
cranial autonomic symptom, conjunctival injection or tearing, is present [3]. Also, the
duration of SUNA attacks seems a bit longer, sometimes extending toward 10 min.
Paroxysms of the chronic pain in HC may last 30 min to 3 days and often are accom-
panied by features suggestive of migraine. Precipitating factors also are varied among
the TACs. Alcohol only appears to be a trigger for cluster and PH, neck movement
only for PH and SUNCT/SUNA, and local cutaneous stimulation only for SUNCT/
SUNA. There are no reliable exacerbating factors in HC. By definition, PH and HC
are completely responsive to therapeutic doses of indomethacin. Consequently, most
guidelines recommend a therapeutic challenge of indomethacin to any patient pre-
senting with a persistently side-locked hemicranial headache disorder.
Migraine is the most common headache disorder seen by physicians, and unilat-
eral pain is typical, while autonomic symptoms may be seen in up to half of patients.
Cluster headache may be occasionally misdiagnosed as episodic migraine and
hemicrania continua as chronic migraine. Duration of pain (migraine attacks 4–72 h)
and the presence of bilateral autonomic complaints when present (more typical of
migraine) should aid in the distinction.
• Cluster headache is the most common TAC, annually affecting 0.1%

(124/100,000) of the general population. It preferentially affects males in a ratio
of approximately 3:1. Age of onset is typically in the second to fourth decade of
life. A slight genetic predisposition may exist, with 5–10% of patients reporting
an affected first-degree relative. Tobacco use is a risk factor for cluster headache
development.
• PH is significantly less common with an annual prevalence of 2/100,000.
• CPH is seen more commonly in women with a 2:1 ratio versus men, while EPH
is evenly distributed between the sexes. No additional risk factors, including any
genetic contribution, have been linked to PH.
• SUNCT/SUNA patients are even rarer, with an estimated population prevalence
of 1/100,000. SUNCT is seen slightly more frequently in men at a ratio of 1.5:1,
and the age of onset of near 50 years is later than either cluster or PH. No genetic
links or environmental risk factors have been identified. The incidence and prev-
alence of HC have not been well established, but the condition appears to be
more common than PH and SUNCT/SUNA but less common than cluster. There
is a slight female preponderance of 2:1, and mean age of onset seems to be in the
30s. There are no known genetic or environmental risks.
262 R.G. Kaniecki
Pain-sensitive intracranial structures including the dura and extracerebral vessels

receive their innervations primarily from the ophthalmic branch of the trigeminal
nerve. Until recently, little was known how this nociceptive circuit was activated in
the TACs. Findings from functional neuroimaging studies, specifically positron
emission tomography (PET) and functional MRI (fMRI), have provided significant
insights into the pathophysiologic underpinnings of the trigeminal autonomic cepha-
lalgias. Hyperactivation of the hypothalamus has been documented to occur ipsilat-
eral to the pain in cluster headache, contralateral in PH and HC, and bilateral in
SUNCT. Hypothalamic involvement may explain the circadian, circannual, and sea-
sonal periodicity noted by many with cluster headache. Hypothalamic connections to
structures along the trigeminovascular nociceptive network may modify nociceptive
signal processing in a facilitatory manner. Activation of areas in the pain matrix and
central opioid circuits has also been identified in these patients through similar func-
tional imaging techniques. Parasympathetic outflow responsible for the cranial auto-
nomic features arises in the hypothalamus, connects in the superior salivatory
nucleus, and then synapses in the sphenopalatine ganglion. Postganglionic fibers
then continue to the lacrimal ducts and nasal mucosa with responses of tearing, nasal
congestion, and eventual nasal drainage. Parasympathetic control of cerebrovascular
tone is also under some hypothalamic control, with activation resulting in vasodila-
tion, plasma protein extravasation, and local release of inflammatory mediators.
Clinical criteria are used to diagnose cluster headache or any of the TACs. Cluster
headache may be divided into episodic (90% of cases) and chronic subtypes.
Episodic cluster involves at least two cycles of headache attacks occurring over
periods of between 7 days and 1 year, separated by pain-free intervals of remission
lasting at least 1 month. Chronic cluster involves attacks occurring without remis-
sion, or with remission periods <1 month, for at least 1 year. These same temporal
criteria are used to subclassify episodic and chronic paroxysmal hemicranias,
although in the case of PH the chronic subtype is much more common.
A detailed history focused on the frequency and duration of pain with a search
for associated non-painful features of the headache disorder is crucial. Neurological
examination with attention to papillary response, fundoscopic appearance, and
visual field assessment should be performed. Typically the physical examination is
normal, although occasionally a Horner’s syndrome may be noted ipsilateral to the
head pain. Imbedded in the formal diagnostic criteria is the requirement that sec-
ondary headache disorders be excluded. Headaches symptomatically similar to
TACs may be seen with pathological lesions in and around the hypothalamus and
pituitary gland. Contrasted brain MRI with attention to the pituitary area must be
examined [9]. Although migraine headache is occasionally confused with cluster
headache due to some symptomatic overlap, the cyclic pattern of cluster and its
shorter attack duration (< 3 h versus 4–72 h for migraine) should aid in the distinc-
tion. Although other primary headaches such as primary stabbing and hypnic head-
ache may present with similar short-duration head pain, these generally lack the
autonomic component. Similarly trigeminal neuralgia may present with brief epi-
sodes of unilateral pain, but unlike the TACs the pain is typically along the second
and third branches of the trigeminal nerve and absent cranial autonomic features.
Trigeminal neuralgia also displays a refractory period following a series of trig-
gered attacks, while SUNCT and the other TACs do not.
Those patients found to have intracranial mass lesions during the work-up of a
trigeminal autonomic cephalalgia might require surgery or other procedures in
order to reduce morbidity and possibly mortality. Those with primary headaches
such as cluster, PH, SUNCT/SUNA, and HC should be treated to reduce morbidity
and improve overall quality of life. These disorders are characterized by excruciat-
ing, unbearable pain that is often challenging to both diagnose and treat. Diagnosis
does provide some measure of reassurance, but rapid introduction of effective
management is required to reduce the overall burden of pain. There is a risk of
mortality with these headache conditions as well, since those with uncontrolled
cluster headache are known to describe suicidal ideations and a small percentage
attempt suicide.
All TACs should be managed with preventive medications, which aim to sub-
stantially shorten the duration of symptomatic periods or reduce overall attack fre-
quency and intensity [15]. Although the episodes of cluster headache may be of
sufficient duration to warrant acute or abortive therapies, attacks of paroxysmal
hemicranias and SUNCT/SUNA are too brief to address acutely. With acute thera-
pies, parenteral and intranasal medication delivery is optimal since oral medication
typically is not rapid enough to suit the needs of the patient. Hemicrania continua is
managed with daily medication, and occasionally acute medication is administered
during painful exacerbations of the underlying continuous discomfort. None of the
treatment options to be discussed were developed to address any specific trigeminal
autonomic cephalalgia. The uncertainty surrounding the true pathogenesis of these
headaches renders it difficult to direct therapeutic research toward a specific target.
Each treatment was developed for other conditions but was found to be helpful in
one or more of these primary headache disorders.
Cluster headache may be managed with both acute and preventive approaches [5].
Following the completion of several clinical trials over the past 10–15 years, a num-
ber of national and international organizations have published evidence-based treat-
ment guidelines [10, 13].
264 R.G. Kaniecki
The most effective treatment options for treatment of an attack of acute cluster
headache are subcutaneous sumatriptan and oxygen inhalation (both level A advice).
Pure oxygen is delivered through a non-rebreather face mask at 100% concentration
and 6–15 l per minute over 10–20 min [4]. Up to 70–75% of patients may respond,
although some describe rapid headache recurrence. Subcutaneous sumatriptan at a
dose of 6 mg is the drug of choice with onset of action as early as 5 min into the attack.
The maximum daily dose of sumatriptan is 12 mg, so many patients may prefer to use
3 mg or 4 mg dosing per attack. Prefilled devices are available in 4 mg and 6 mg
strengths, but lower doses may be drawn from a 6 mg vial. Although the onset is not
as rapid, there is level A advice supporting the use of zolmitriptan nasal spray at a dose
of 5 mg (maximum daily dose 10 mg). Level B advice is available for sumatriptan
20 mg nasal spray (maximum daily dose 40 mg) and zolmitriptan 5 mg tablets (maxi-
mum daily dose 10 mg). All triptans are contraindicated in the presence of coronary,
cerebral, or peripheral vascular disease, uncontrolled hypertension, or vasospastic
angina. Side effects common to the class are chest pressure, throat or jaw tightness,
and flushing. Subcutaneous sumatripan is the most likely formulation to generate
these adverse events while it also may cause local site reactions, while the nasal spray
preparations are often associated with an unpleasant taste. The only medication other
than subcutaneous sumatriptan to have an FDA indication for acute cluster is paren-
teral dihydroergotamine, which generally is delivered intravenously (1 mg three times
daily over 3 days) in the attempt at truncating a cycle of cluster headache. Nausea is a
common side effect and generally necessitates co-administration with prochlorpera-
zine 10 mg or metoclopramide 10 mg intravenously. Chest or abdominal pain and
muscle cramping are other adverse events. Intranasal lidocaine (4–10% via drops or
spray) is a less efficacious alternative to oxygen or triptan therapy and may be used
multiple times per day. The best results are achieved when the treatment is adminis-
tered in the supine position with the neck extended, the head turned toward the side of
pain, and the medication placed in the nostril ipsilateral to the pain. Nasal stuffiness,
throat numbness, and hoarseness are sometimes noted.
Prevention of cluster headache may be divided into short-term and long-term
categories. Short-term measures are more rapidly effective and may be used as pri-
mary prevention in cases where patients report cycles lasting less than 1 month. In
most cases, patients have cycles lasting 6–12 weeks, and short-term preventive
measures are considered a bridge to long-term prophylaxis. Corticosteroids are the
most common measures used in the short term. Prednisone may be initiated at
80 mg per day and tapered by 10–20 mg every 2–3 days to provide coverage over
10–14 days. Sometimes the course may be repeated if the headache cycle ceases but
immediately returns. Dexamethasone at 12 mg per am, tapered by 4 mg every
3–4 days over a similar duration, is an alternative. Methylprednisolone at 250–
500 mg daily over 3–5 days can be more effective than prednisone. Insomnia,
moodiness, and increased appetite may be seen with short-term steroid administra-
tion, while hiccups are occasionally noted. Greater occipital nerve blockade with a
local anesthetic (lidocaine or bupivacaine) mixed with corticosteroid (betametha-
sone, dexamethasone) has been shown to be effective in truncating a cluster cycle
(level B advice) [17]. Local pain, bruising, and scalp numbness may be reported
following the injections, but most patients tolerate these procedures quite well. The
duration of response far outlasts the predicted therapeutic response of the agents
delivered, with effective results lasting weeks to months. The injections may be
repeated every 1–2 weeks initially if necessary. Prior to the development of the
triptans, patients were treated with scheduled ergotamine (1–3 mg daily) over a
maximum period of 4–6 weeks, but this eliminates the option of using any triptan
for acute attacks. Nausea, abdominal or chest pain, and muscle cramping are com-
mon with the ergot derivatives. The agent of choice for long-term prevention is
verapamil (level C advice). The immediate-release version may be started at 80 mg
twice daily and advanced over 1–2 weeks toward 240–480 mg total daily dosing
[11]. The sustained-release option is less bioavailable and may be started at 180 mg
and advanced over 1–2 weeks toward doses of 240–720 mg. Doses greater than
240 mg require electrocardiographic monitoring for possible heart block. Common
side effects are constipation, hypotension, and pedal edema. Other options for long-
term prevention of cluster headache achieving level C advice are lithium carbonate
at a dose of 900 mg and melatonin at a nightly dose of 10 mg. The lithium requires
monitoring of serum drug levels (best at 0.4–0.8 nmol/L) and renal functions. Side
effects include tremor, metallic taste, and hypothyroidism. In refractory cases, topi-
ramate in the range of 100–200 mg has been shown to be effective in open-label
trials. Paresthesias, cognitive impairment, mood changes, and appetite suppression
are the most frequently reported adverse events.
The diagnosis and management of paroxysmal hemicrania and hemicrania con-
tinua are intertwined since included among the formal ICHD criteria for both is the
requirement for a complete response to indomethacin. Typically dosing begins with
25 mg tid for 1 week, then advancing to 50 mg tid, and then 75 mg tid weekly until
a response is achieved. Due to side effects of nausea or dyspepsia, most dose indo-
methacin with meals, and many prescribe proton pump inhibitors for those patients
on long-term therapy. Monitoring for renal impairment or gastrointestinal bleeding
should be undertaken periodically, initially after a treatment period of 3 months and
eventually every 6–12 months while on stable dosing. Additional adverse events
include tinnitus, dizziness, diarrhea, and development of a different headache. The
prevention of SUNCT/SUNA is significantly more challenging. Given the rarity of
the disorder, no randomized controlled clinical trials have been performed.
Lamotrigine may occasionally be of benefit, beginning at 25 mg daily and gradually
raising the dose over the first month toward 100–150 mg. More rapid escalation
may increase the risk of serious rash complications. If such doses are unhelpful,
further titration toward 200–400 mg daily over the second month may be indicated.
Tolerability issues aside from rash include dizziness, fatigue, and moodiness. There
is no available abortive treatment for the acute attacks of SUNCT/SUNA.
The use of opioids in the management of TACs should be avoided. There is no
data to document benefit over the list of available therapies outlined above. Since
many of these disorders are chronic, there are clear risks of opioid dependence and
underlying headache aggravation through a potential medication overuse or
“rebound” element. Only in rare cases of failure or contraindication to existing ther-
apies should opioids be prescribed.
266 R.G. Kaniecki
The management goals of episodic cluster headache are to shorten the duration of
headache cycles, lower the frequency of attacks during the cycle, and effectively treat
those acute episodes breaking through preventive measures. In the case of the first
cycle, the patient should be evaluated in the office and undergo diagnostic work-up. In
cases of recurrent cluster headache cycles, treatment should be initiated immediately.
Once the cycle has started, the corticosteroid is prescribed and dosed in the morning,
while the melatonin is started at night. For those with cycles previously lasting greater
than 4 weeks, verapamil is co-administered with these agents in a twice-daily dosing
schedule. A baseline electrocardiogram is arranged and repeated 2 weeks following
each dose escalation beyond 240 mg per day. Unless prior therapeutic failure has been
documented, arrangements for an oxygen tank with non-breather mask are made. In
the absence of contraindications, subcutaneous sumatriptan at a dose of either 4 mg or
6 mg is prescribed. If the patient has significant cardiovascular disease risk factors, a
functional cardiac evaluation will be required prior to any triptan prescription. Such a
process would involve work-up similar to a preoperative evaluation, and should that
return unremarkable, many providers may elect to deliver the first dose in the office.
Since most health plans restrict the quantity of triptan doses allowable per month, a
prior authorization for quantity limit exception should be pursued. If subcutaneous
sumatriptan is ineffective or poorly tolerated, nasal administration of sumatriptan, zol-
mitriptan, or lidocaine are subsequent options for acute attacks. Should the cycle per-
sist, short-term options include repeating the corticosteroid course and/or delivering
ipsilateral greater occipital nerve blocks. At that time, the long-term prevention with
verapamil should be escalated toward 360–720 mg as necessary and tolerated [18]. In
cases of partial response, lithium may be added to verapamil, while in cases of nonre-
sponse, the verapamil should be tapered and discontinued. Topiramate is typically
used if both verapamil and lithium fail. Subsequent medical options without clear
evidence of benefit include valproate, gabapentin, amlodipine, and diltiazem.
By definition, all patients with the paroxysmal hemicranias or hemicrania continua
should respond to adequate doses of indomethacin. Patients should expect to take indo-
methacin for years, and in many cases, the treatment is lifelong. Sustained efficacy of
indomethacin without tachyphylaxis is to be expected. Approximately half of patients
will be able to reduce their indomethacin dosing by 50% over time, so attempts to
lower dosing should be made every 6–12 months. Other measures may be necessary in
those that fail to tolerate the indomethacin despite dosing with meals and coverage with
proton pump inhibitors or in those with medical conditions (renal insufficiency, signifi-
cant gastrointestinal conditions, treatment with anticoagulation) which prohibit its use.
Additional treatment options with occasional reported partial benefit include aspirin,
celecoxib, naproxen, melatonin, topiramate, acetazolamide, and verapamil. Occipital
nerve blocks may also be attempted. In cases of SUNCT/SUNA refractory to lamotrig-
ine, possible options include topiramate, gabapentin, or hospital admission for intrave-
nous phenytoin (250 mg one to three times daily) or lidocaine (1–4 mg/kg/h).
In the past, surgical ablative procedures were performed in cases of refractory clus-
ter headache and also occasionally in cases of SUNCT/SUNA [8]. These procedures
had targeted the first branch of the trigeminal nerve or locations along the parasympa-
thetic pathway such as the sphenopalatine ganglion, greater superficial petrosal nerve,
or the nervus intermedius. Results were almost universally disappointing, and compli-
cations such as corneal ulceration and anesthesia dolorosa were often problematic.
Potential new therapies are arising in the field of neuromodulation. Most of the data
has been accumulated in patients with refractory chronic cluster headache. Occipital
nerve stimulators, vagal nerve stimulators, and more recently sphenopalatine ganglion
stimulators all have data to support significant responses in greater than half of treated
subjects [1, 16]. A number of studies investigating these options are in process. Deep
brain stimulation of the posterior hypothalamus has been shown to be helpful in cases
of refractory cluster, but major adverse events including potential mortality have lim-
ited its usefulness (Tables 23.1, 23.2, 23.3 and 23.4).
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Migraine Variants
24
Robert L. Merrill
Pearls of Wisdom
• Migraine variants represent a group of headache disorders that have
migrainous characteristics and also which are accompanied by neurologi-
cal symptoms that are not recognized as “classic” migraine symptoms.
• While it is generally recognized that these conditions represent primary
headache disorders, the clinician should go beyond the diagnostic workup
accepted for the primary headache disorders, because the potential for
these headaches being secondary to central organic causes is greater.
• Migraine variants can be classified into:
–– Late-life migraine
–– Basilar-type migraine
–– Ophthalmoplegic migraine
–– Hemiplegic migraine
–– Retinal migraine
–– Progressive migraine
–– Primary stabbing headache
–– Exertional migraine
–– Vestibular migraine
• Patients are living longer and are often on multiple medications that are not
being managed appropriately. This is leading to an increase in late-life
migraine sufferers in our pain clinics.
R.L. Merrill, DDS, MS

UCLA School of Dentistry, Los Angeles, CA, USA
e-mail: rmerrill@ucla.edu

DOI 10.1007/978-3-319-51508-3_24
270 R.L. Merrill
24.1 Introduction
The discipline of orofacial was recognized as a dental specialty by the Commission

on Dental Accreditation in 2010, and the first programs were accredited in 2011.
The specialty of orofacial pain bridges the gap between medicine and dentistry and
serves a population of patients who have pain problems that neither discipline has
been effective in diagnosing or treating.
The practitioners of orofacial pain are at the cutting edge of both dentistry and
medicine because they are able to diagnose and successfully treat disorders that
have long been and generally still remain a puzzle to both professions. Dentistry
is slowly making inroads into the field of headache through the training that is
being provided in the various orofacial pain programs. Graduates of these pro-
grams add credibility to the important role that dentistry needs to play in address-
ing head and neck pain. Unfortunately, some dentists advocate unscientific
diagnostic and treatment procedures claiming they can cure a migraine headache
without being able to perform a neurological examination or being able to actu-
ally make an accurate diagnosis of the various headache conditions that may be
seen in an orofacial pain practice. This tends to diminish the regard of dentistry in
the medical community. This is a very dangerous situation that needs to be rem-
edied by recognizing that practitioners of orofacial pain should be board certified
and trained to medically assess and treat headaches. As we gain better understand-
ing of the neuroanatomy, neurophysiology, and neurobiology of pain, we are able
to include more orofacial pain conditions in the general nosology of pain and
provide explanations for many previously enigmatic orofacial pain conditions.
This is certainly the case with orofacial neuropathies.
Neurovascular disorders are an important part of orofacial pain, because the
prevalence of headache is high (64% in the UCLA OFP clinic) in OFP patient
population, and the headache is a significant part of their chronic pain problems
[1]. Temporomandibular disorders are often associated with concomitant head-
aches. Many referrals to Temporomandibular Joint (TMJ) clinics come from phy-
sicians who have been treating the headache without success and refer the patient
to the dentist on the assumption that the patient has a “TMJ headache.” In addi-
tion, dentists treating TM disorders are often blindsided by patients who have a
headache disorder such as chronic migraine or “facial migraine” and find that
focusing only on the TM symptoms does not relieve their patient’s pain. Treating
one disorder without recognizing and addressing the other usually results in sub-
optimal outcomes for the suffering patient. Additionally, the general dentists may
not be aware that the pain/headache condition could be the result of a CNS lesion
that has not been recognized. This paper will address the “migraine variants” that
the orofacial pain specialist should be aware of and consider as he/she delves into
the mystery of chronic orofacial pain.
For the most part, the diagnosis of migraine variants is a diagnosis of exclusion.
Although most of these conditions are primary disorders, they could be secondary
to a more serious and/or life-threatening condition. Therefore, it is important for the
24 Migraine Variants 271
orofacial pain specialist to recognize and do an appropriate workup or make an

appropriate referral to specialist who can take care of the patient. Migraine variants
may be characterized by the following symptoms:
• Confusion
• Dysarthria
• Atypical sensory, motor, or visual aura
• Focal neurologic deficits
• Paroxysmal episodes of prolonged visual auras
• Gastrointestinal (GI) manifestations
• Other constitutional symptoms, with or without a headache
The International Headache Society (IHS) published The International

Classification of Headache Disorders (ICHD-II) in 2004. This document updated and
refined the first classification system published in 1988 [2]. Subsequently, the IHS has
published the ICHD-III beta version that has made significant changes to the 2004
version. The changes primarily were informed by research, and some of the disorders
classified in the ICHD-II have been reassigned, recategorized, or dropped [3]. This
does not mean, however, that the disorders do not exist but that there is not enough
evidence to support including them in the updated classification system at this time.
In the 28 years since the first publication, great strides have been made in refining the
understanding of headache nosology, pathophysiology, and management.
Migraine variants represent a group of headache disorders that have migrainous
characteristics but also which are accompanied by neurological symptoms that are
not recognized as “classic” migraine accompaniments. While it is generally recog-
nized that these conditions represent primary headache disorders, the clinician
should go beyond the diagnostic workup accepted for the primary headache disor-
ders because the potential for these headaches being secondary to central organic
causes is greater. Silberstein and Saper in the first and second editions of their
Handbook of Headache Management listed and discussed their choice of migraine
variants [4]. The list on their handbook included:
• Late-life migraine
• Basilar-type migraine (migraine with brain stem aura)
• Ophthalmoplegic migraine (recurrent painful ophthalmoplegic neuropathy)
• Hemiplegic migraine
• Retinal migraine
• Progressive migraine
• Primary stabbing headache (icepick pain)
• Exertional migraine
• Vestibular migraine
Some of these conditions have been reclassified in the ICHD-III beta and will be
discussed in more detail below in relation to the ICHD-III beta classification system.
272 R.L. Merrill
24.2 E
tiology, Epidemiology, Diagnostic Criteria,
and Treatment of Migraine Variants
24.2.1 Late-Life Migraine
The average age of the population in the orofacial pain clinic is getting older, and
the likelihood of seeing elderly patients with headache is significantly increased.
Our patients are living longer and are often on multiple medications that are not
being managed appropriately. Epidemiological studies have shown that the preva-
lence of migraine decreases in the above 50 years of age group. Females who suf-
fered from migraine through their productive year will usually see a decline in
migraine after menopause, but male migraineurs also see a decline in migraine epi-
sodes, as they get older.
A major complication in migraine in the elderly is the fact that elderly patients
may be taking medications or combinations of medications that may cause head-
ache. The clinician should be aware of all medications taken by an elderly patient
whose presenting complaints may include headache because the medications may
be responsible for the pain they are experiencing. This may be due to sensitivity to
a medication, misuse of a medication, or medication interactions. The elderly may
experience toxic side effects from “appropriately dosed” medications due to their
body’s decreased ability to metabolize the medications. Often, the elderly have to be
given lower doses of a given medication to avoid toxicity or untoward side effects.
New-onset or persistent headache is always a red flag in the elderly, and the
workup needs to include neuroimaging since the likelihood of the headache being
secondary to a structural lesion is significantly higher for the elderly than for the
young. Headache due to disease is more common in the elderly than in the young.
The onset of a new headache condition in the elderly patient is certainly a red flag
that needs to be pursued in depth and other potential causes of the headache
excluded.
Fisher in 1980 [5] described the phenomenon of late-life migraine as attacks of
migraine-associated neurological symptoms without the development of headache.
He proposed that the symptoms were due to the same neurological process as
migraine but without pain. He noted that the attacks would last up to 72 h (similar
to migraine) and may also be accompanied by the various manifestations of aura,
including visual scotomas, paresthesias, or other sensory and motor symptoms that
accompany migraine. These symptoms could also occur in patients who did not
have a prior history of migraine.
As indicated at the first of this paper, most of the headaches in this section are
diagnosed by exclusion, and this is certainly the case with late-life migraine.
The differential diagnoses should include:
• Stroke
• Clotting disorders
• Central lesion
• Medications or substances
The workup must include:
1. Neurological assessment
2. Head and neck physical assessment
3. Review of all medications and pattern of use
4. CT and/or MRI/MRA
24.2.2 Migraine with Brain Stem Aura [3] (Formerly Basilar-Type

Migraine or Basilar Migraine)
Bickerstaff was one of the first to write about basilar migraine, and the condition has
been known as Bickerstaff syndrome [6]. In his paper, he noted that all of the
patients were under 35 years of age and most were women. He also noted that the
attacks were generally infrequent and that the patient also could have headache with
normal non-brain stem aura. The aura phenomena described by Bickerstaff included
visual disturbances in both fields of vision (compare with retinal migraine below),
diplopia, bilateral limb paresthesia, perioral tingling, dysarthria, vertigo, tinnitus,
and ataxia. These symptoms would last 20–30 min and would be relieved by sleep.
Migraine with brain stem aura can affect children and teens but tends to change
to other types of migraine with age. It is less common in patients over the age of
50 years. The visual auras are bilateral and include scintillating scotomata, blurring
vision, or total blindness. Double vision is not common but may occur if sixth cra-
nial nerve paresis is part of the aura. Sensory symptoms may be bilateral and sym-
metric but also may alternate from side to side in a hemisensory pattern. These
sensory changes can involve the oral region and extend throughout the arms and
legs. Motor weakness has been reported in more than 50% of the cases. Changes in
level of consciousness are de rigueur. These changes range from a sleep state to
syncope and even coma.
The headache itself is bilateral (rarely unilateral) in the frontal or occipital
region, is described as throbbing, and is accompanied by photophobia, phonopho-
bia, and nausea and vomiting.
The ICHD-II classification renamed basilar migraine, basilar-type migraine, and
included it under rubric of migraine with aura. The ICHD-III beta now classifies this
migraine variant as migraine with brain stem aura [3]. Because of the remarkable
attending symptoms, this migraine variant was originally thought to be due to a
spasm of the basilar artery resulting in ischemia, since many of the accompani-
ments, such as dizziness, ataxia, or altered states of consciousness, reflected brain
stem dysfunction. Bizarre behavior and obscene utterances have been noted as well
as slowed EEG recordings. Now, it is thought that the symptoms of this variant of
migraine are due to neuronal dysfunction either with or without ischemia.
The aura symptoms include visual, sensory, and/or speech symptoms, and all are
fully reversible. There are no motor symptoms associated with this condition. If
motor symptoms are observed, the headache should be classified as hemiplegic
migraine.
274 R.L. Merrill
The symptoms include two or more of the following [3]:
1. Dysarthria
2. Vertigo
3. Tinnitus
4. Hypacusis
5. Diplopia
6. Ataxia
7. Decreased level of consciousness
Additionally, the headache should have at least two of the following four
characteristics:
1. At least one aura symptom spreads gradually over 5 min, and/or two or more
symptoms occur in succession.
2. Each individual aura symptom lasts 5–60 min.
3. At least one aura symptom is unilateral.
4. The aura is accompanied, or followed within 60 min, by headache.
24.2.2.1 Pathophysiology
The pathophysiology of migraine with brain stem aura is still unclear but is consid-
ered to be related to neuronal dysfunction with or without vasoconstrictions, e.g.,
spreading depression in the brain stem, similar to cortical spreading depression
associated with migraine with aura.
24.2.2.2 Treatment
Early on, treatment of migraine with brain stem aura was limited to medications that
did not cause vasoconstriction due to earlier presumptions that this migraine variant
was due to vasoconstriction of the basilar artery. Medications such as triptans,
DHE- 45, cafergot, isometheptene, methergine, or other vasoconstrictors were
avoided. Although this particular issue has been resolved, there is still a lack of
research showing that their use is safe with this variation of migraine. Abortive
medications such as opioids may be used. Prophylactic medications such as depak-
ote, gabapentin, and topiramate are also useful.
24.2.3 Ophthalmoplegic Migraine
This condition is now termed recurrent painful ophthalmoplegic neuropathy and is

no longer classified as a migraine variant.
24.2.4 Hemiplegic Migraine/Familial Hemiplegic Migraine
The description of this migraine disorder is migraine with aura including motor
weakness. Familial hemiplegic migraine (FHM) also includes motor weakness, but
there must be at least one first- or second-degree relative that has migraine aura
including motor weakness. Familial hemiplegic migraine (FHM) is an autosomal

dominant genetically heterogeneous form of migraine with aura that is character-
ized by motor weakness. Researchers have identified four missense mutations in the
CACNA1A gene on chromosome 19p. The gene encodes for an alpha 1A subunit of
the P/Q type voltage-gated calcium channel [7, 8]. This channel regulates release of
specific neurotransmitters such as glutamate. The attacks may represent typical
migraine with or without aura and severe attacks with prolonged aura that may last
from several days to weeks. Additionally, the patient may experience impaired con-
sciousness ranging from confusion to profound coma. The headache phase of the
attack may be absent, precede, or start with the hemiparesis. The hemiparesis may
be abrupt and mistaken for a stroke.
The differential diagnosis list for hemiplegic migraine includes:
• Focal seizures
• Stroke
• Coagulopathies
• CADASIL
• MELAS
The ICHD-II subdivides hemiplegic migraine into sporadic and familial types.
The ICHD-III subclassifies familial hemiplegic migraine into type 1, type 2, type 3,
other loci, and sporadic hemiplegic migraine. This headache should be thoroughly
investigated including family history by a specialist.
24.2.4.1 Treatment
Typically triptans are best avoided during the aura phase. Flunarizine or topiramate
may be the best options for prophylactic treatment.
24.2.5 Retinal Migraine
Retinal migraine is described as repeated attacks of monocular visual disturbance,

including scintillations, scotomata, or blindness that are associated with migraine
headache. One of every 200 migraineurs has monocular visual symptoms with their
headache. The headache is preceded by or accompanies reversible visual impair-
ment or blindness in one eye. The visual impairment will last less than 1 h.
Pathophysiologic studies have demonstrated retinal or optic nerve hypoperfusion
from spasm of the central retinal or ophthalmic artery. Burger and associates
reported amaurosis fugax episodes due to vasoconstriction during the retinal
migraine attacks [9]. Visual symptoms of retinal migraine include unilateral qua-
dratic and altitudinal or total grayout, whiteout, or blackout visual loss. Some
patients report a concentric constriction of the monocular visual field proceeding
from the periphery to the center. There may be total visual loss or a small part of the
visual field preserved. It is presumed that the visual symptoms are due to the retinal
or ophthalmic artery. Central retinal artery occlusion and branch retinal artery
occlusion can cause infarction of the entire retina or of the affected retinal sector.
276 R.L. Merrill
The retinal artery usually has two major branches: one covering the upper half and
the other the lower half of the retina. An altitudinal scotoma in one eye can result
from occlusion of one of the branches. A transient occlusion of the retinal artery
whether by vasospasm or by emboli causes amaurosis fugax with a browning or
blackout of the vision in one eye for about 10 min. This has been described as being
“like a window shade” moving down or up over the eye. Amaurosis fugax may be a
warning sign for an impending retinal or cerebral infarct.
The differential diagnosis should include:
• Embolic disease
• Ischemic optic atrophy
• Central organic causes
• Retinal spreading depression (part of the spreading depression of migraine)
The examination should include an ophthalmologic examination, CT/MRI, and

carotid ultrasound studies.
24.2.6 Progressive Migraine (to Chronic)
Medication overuse has been associated with the development of chronic headache,
including migraine. This migrainous headache has been variously called progres-
sive or transformational migraine but is now called chronic migraine in the ICHD-
III beta manual. The most common cause of chronic migraine is overuse of
symptomatic medications. Chronic migraine is described as a headache occurring
on 15 or more days per month for more than 3 months and has the features of
migraine headache on at least 8 days per month [2, 3]. The headache can be either
tension-type-like or migraine-like and with or without aura. Around 50% of patients
with chronic migraine see the headache revert to an episodic headache with disuse
of the overused drug. In those patients who are overusing medication and have
chronic migraine, they should be given both the diagnosis of chronic migraine and
medication overuse headache [3].
Treatment involves withdrawing the offending medication and starting the
patient on an appropriate prophylactic medication such as Topamax. Onabotulinum
toxin has been approved as a treatment for chronic migraine, and numerous studies
have shown it to be very effective in treating the headache [10, 11].
24.2.7 Primary Stabbing Headache (Jabs and Jolts Syndrome)
What had been previously designated as icepick pain, jabs and jolts, or ophthalmo-
dynia periodica is categorized by the ICHD-III beta as Primary Stabbing Headache.
The pain is described as transient localized stabs of pain in the head, occurring
spontaneously and in the absence of organic disease of underlying structures or of
the cranial nerves. The diagnostic criteria include sharp or stabbing pain, usually in
the V1 distribution of the trigeminal nerve. The stabs last for a few seconds and may
recur spontaneously several times per day. The stabs or “jabs and jolts” may move
from one area to another on the same side or move to the opposite side. The reason
for including this headache in the group of migraine variants is that 40% of
migraineurs experience these stabbing pains [12, 13]. They may occur during or
between migraine attacks. Jabs or Jolts occurring in the temple, face or external ear
may be misdiagnosed as a TMJ disorder or trigeminal neuralgia by an unsuspecting
clinician. Although the mechanism is unclear, the condition has been found to
respond to indomethacin and possibly other NSAIDs [14].
• Myofascial pain
• Epicrania fugax
• Nummular headache
• Occipital neuralgia
Treatment for primary stabbing headache includes indomethacin 25–50 mg three

times/day. This has been found to be effective in 65% of patients.
24.2.7.1 Epicrania Fugax

Although not related to migraine, epicrania fugax can be confused with primary
stabbing headache that has been associated with migraine. This disorder is char-
acterized by brief paroxysmal stabbing head pains that radiate in a linear or zigzag
trajectory across the surface of one hemicranium, although a case series has been
reported where the pain crosses to the opposite hemicranium [3, 15]. The recur-
rent stabbing pains last for 1–10 s. Treatment involves neuromodulators, indo-
methacin, tricyclic antidepressants, nerve anesthetic blockades, and trochlear
steroid injections [16].
• Occipital neuralgia
• Primary stabbing headache
• Nummular headache
• Trigeminal neuralgia
• Myofascial pain
24.2.8 Exertional Migraine (Primary Exercise Headache)
Hippocrates may have been the first person to recognize the headache disorder
when he wrote, “one should be able to recognize those who have headache from
gymnastic exercises, or walking, or running, or any other unseasonable labor, or
from immoderate venery.” The ICHD-III beta continued to include this headache
entity in the fourth category of other primary headaches. The headache is character-
ized by severe transient headache that occurs after an exertional or straining
278 R.L. Merrill
activity. The diagnostic criteria include a pulsatile headache lasting from 5 min to
48 h that was brought on by or occurred only during or after physical exertion. The
first occurrence of this headache should always be followed up with imaging studies
to exclude subarachnoid hemorrhage or arterial dissection. It has been reported to
occur particularly in hot weather or at high altitude.
The pathophysiology may involve arterial dilatation since the headache develops
after exertion and on hot days; however, there is no objective evidence of this.
Basoglu and associates, using SPECT (single photon emission computed tomogra-
phy), noted frontal hypoperfusion in a boy with exertional headache, but the signifi-
cance of this is uncertain. Paulson has suggested that acute venous distension may
be a possible mechanism [17, 18]. Pheochromocytoma has been associated with
exertional headache.
Differential diagnosis should include:
• Cardiac ischemia
• Intracranial vascular disorders
• Pheochromocytoma
• Carotid artery stenosis
Treatment should involve undertaking exercise gradually and progressively, since

as physical conditioning progresses, the headache occurrences tend to dissipate.
Exertional headaches respond to indomethacin in the majority of cases [19, 20].
24.2.9 Vestibular Migraine
This is a migraine-like headache that is associated with vertigo or dizziness. The

patient has a past history of migraine fulfilling the migraine criteria with or without
aura. The vestibular symptoms are moderate to severe intensity and will last 5 min
to 72 h. This disorder may also be associated with transient auditory symptoms and
susceptibility to motion sickness. Although vertigo is also reported by more than
60% of patients with migraine with brain stem aura, the ICHD-III requires at least
two brain stem symptoms in addition to the visual, sensory, or dysphasic aura symp-
toms to make the diagnosis of vestibular migraine [3]. Vestibular migraine and
Meniere’s disease may be an inherited symptom cluster, and migraine headaches,
photophobia, and auras are common in Meniere’s attacks. Additionally, in the first
year of symptom onset, it may be difficult to distinguish the difference between
vestibular migraine and Meniere’s disease [3, 21].
This headache requires a full neurological assessment because it is important to
establish a correct diagnosis. The differential diagnoses include:
• Benign paroxysmal positional vertigo (BPPV)

• Meniere’s disease
• Transient ischemic attacks (TIAs)
• Fluid leaks in the inner ear
• Vestibular nerve irritation
Treatment is aimed at preventing the attacks. Typical medications include:
• Beta-blockers
• Calcium channel blockers
• Tricyclic antidepressants
• Gabapentin
• Clonazepam
• Acetazolamide
• Topiramate
• Oxcarbazepine
References
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Part IX
Health Care Approaches in Orofacial
and Widespread Pains
Interdisciplinary and Multidisciplinary
Approaches to Orofacial Pain Care 25
Shawn McMahon
Pearls of Wisdom
• Biomedical and biopsychosocial models are two approaches to health care
that have been proven effective when utilized in the appropriate situation.
Health-care providers must understand that chronic pain is a disease of the
person and that a traditional biomedical approach cannot adequately
address all of the individual pain-related physiological, psychological, and
social needs of this patient population.
• Chronic pain patients generally present with complex, multimodal prob-
lems that often involve two or more coexisting chronic pain conditions
(e.g., chronic headaches, chronic fatigue syndrome, fibromyalgia, inflam-
matory bowel disease, interstitial cystitis, temporomandibular joint dys-
function, vulvodynia, and gastric reflux disease). They often describe
disturbed sleep, increased stress, anxiety, depression, and even anger
resulting in a decreased quality of life. With so many overlapping factors,
it makes sense that current literature supports a “whole person” approach
to chronic pain diagnosis and management.
• Current literature describes various models to address chronic pain using a
multimodal approach. Although they differ in areas such as organization,
structure, format, and cost, they do have common core features:
–– A biopsychosocial approach to diagnosis and care that not only
addresses the associated biology but also the psychological and social
aspects of the pain condition
S. McMahon, DDS, MS
Orofacial Pain Clinic, Joint Base San Antonio, San Antonio, TX, USA
Uniformed Services University of the Health Sciences, Bethesda, MD, USA
e-mail: shawnmcmahondds@gmail.com
© Springer International Publishing Switzerland (outside the USA) 2017 283

J.N.A.R. Ferreira et al. (eds.), Gene Therapy for Radiation-Induced Salivary
Hypofunction, DOI 10.1007/978-3-319-51508-3_25
284 S. McMahon
–– Providers from multiple disciplines working in an integrated fashion

with shared treatment goals
–– Goals: to reduce effects of pain, improve function, and achieve indepen-
dence from the health-care system
• Multidisciplinary care involves care provided by health-care providers
from several disciplines which may, or may not, be coordinated, and treat-
ment may occur with different goals in parallel rather than an integrated
approach.
• Interdisciplinary care involves a team of health-care providers from differ-
ent specialties that play complementary roles that when implemented
together enhance patient care.
25.1 Introduction
As evidenced by the topics presented in this clinical guide, orofacial pain disorders
comprise a wide range of conditions. Thus, when evaluating an orofacial pain
patient, the clinician may face a formidable diagnostic challenge. The differential
diagnoses for an orofacial pain complaint may include conditions from a variety of
categories: musculoskeletal, inflammatory, infectious, neurovascular, neuropathic,
neoplastic, metabolic, endocrine, and autoimmune disorders [1]. Patients with oro-
facial disorders may present with a complex medical and psychosocial clinical his-
tory, which may include acute or chronic symptoms, and present as single or
coexisting disorders that may share perplexing interrelationships that involve psy-
chosocial behavioral factors as well as underlying physical pathology.
A successful treatment is frequently compromised by the chronic nature of the
disease and by long-standing maladaptive behaviors, attitudes, and lifestyles that
may actually perpetuate or result from the illness. Factors such as disability, chemi-
cal dependency, inadequate nutrition, sleep disturbances, and countless others are
beginning to be studied and understood. Failure to help the patient change these
factors often plays a major role in failure to obtain successful long-term manage-
ment of these disorders.
Traditional medicine often fails to educate and support the patient in making
these changes. Even when these problems are identified by the clinician or the
patient, the ability to help deal with factors involved is limited by the nature of den-
tal or medical training, the system in which dentistry or medicine is practiced, and
the complex nature of each factor. In addition, the traditional approach to treatment
employs a biomedical approach (Fig. 25.1), is usually singular in nature, and varies
according to the clinicians’ favorite theory of etiology (Table 25.1).
When history and examination do not indicate a clearly identifiable etiology for
a patient’s pain (i.e., trauma, infection, neoplasm, etc.), patient care should be
approached with a comprehensive biopsychosocial mind-set to enable the best pos-
sible prognosis (Fig. 25.2) (Table 25.2).
25 Interdisciplinary and Multidisciplinary Approaches to Orofacial Pain Care 285
Disease Illness
Wellness or Intervention Wellness
injury
disorder
Fig. 25.1 The biomedical model is a conceptual model of illness that excludes psychological and
social factors and includes only biologic factors in an attempt to understand a person’s medical
illness or disorder [21]
Table 25.1 Biomedical model

Definition: assumes etiology is disease based and effective treatment is a medical approach
Advantages:
Embraces a simpler or more fundamental level of care
Effective in the management of acute illnesses that have predictable outcomes (i.e., bone
fracture)
Suitable for health-care providers focused on similar individual areas of a patient’s health
Potentially less expensive
Disadvantages:
Does not account for situations involving persistent pain even after damaged tissue has
healed
Focuses on disease mechanisms and does not take the person’s thoughts, emotions, or social
effects into consideration
Table 25.2 Biopsychosocial model

Definition: combines the physiological, psychological, and social aspects of the pain experience
Advantages:
Comprehensive, often independently unique, care that fits individual physiological,
psychological, and social needs and wants
Often utilizes interdisciplinary or multidisciplinary care
Incorporates patient, family, and health-care provider participation to promote patient
“ownership” and social support for well-rounded care (i.e., avoiding or reducing patient
catastrophizing)
Defines how and why psychological disorders or social factors can sometimes result in
physiological problems
Promotes good mental and emotional health in order to maintain a healthy
lifestyle – cost-effective
Disadvantages:
Assumes that all pain conditions are biopsychosocial; however, the model is not necessarily
applicable to every condition (i.e., acute pain)
Can be confusing and misleading method to use correctly. Requires training beyond the
biomedical approach
Could result in delayed care. It can be impractical and time-consuming when trying to
analyze and manage a patient’s problem
Potentially more expensive
286 S. McMahon
e Frie
eas n
Dis ry fam ds
i n j u i
beli ly
efs
y y
og olog
ol Bi
Bi
Illness Wellness
Intervention
Stress
anxiety
depression
anger
Fig. 25.2 The biopsychosocial model encompasses the complex interactions between biology,
psychological states, and social conditions that bring about and/or maintain dysfunction [1]
The past president of the American Society of Physical Medicine and Rehabilitation,
William Fowler, states that “Schools continue to emphasize diagnostic skills, quick
complete cures, and the patient with acute disease as the teaching model for medical
students and house staff…. as a result, clinical management as well as research and
teaching regarding chronic disease and rehabilitation tends to take second place and is
often done outside the usual academic channels.” This may be partially because the
practice of health care focuses on evaluation and management of a chronic illness by
a single primary practitioner. It is estimated that 30–50% of patient presentations to
primary care will not yield a specific diagnosis. Furthermore, when distressed patients
continue to shop for care from a multiple providers, they are at increased risk for iat-
rogenic injury and cost to themselves and the health-care community [2]. It may be
unrealistic to expect a single clinician to address the multitude of contributing factors
that may be present in a patient with chronic pain.
25.2 Defining Multimodal Approaches to Orofacial Pain Care
There are various ways in which a comprehensive approach may be implemented.

Evidence supports both multidisciplinary and interdisciplinary approaches to care.
The terms multidisciplinary and interdisciplinary are often used interchangeably;
however, there are subtle but important differences.
Multidisciplinary care is defined as care provided by specialists from several
disciplines which may, or may not, be coordinated, and treatment may occur with
different goals in parallel rather than an integrated approach (Fig. 25.3). In this
model each provider has a clearly defined role in the overall care of the patient.
They contribute individualized expertise in relative isolation from one another
under the overall care manager (generally a physician) [3–5] (Table 25.3).
Primary
care
Sleep
Oral
medicine
surgery
Physical
Physical OFP medicine &
therapy clinician rehab
&
patient
Behavioral
Neurology
health
Rheumatology Otolaryngology
Fig. 25.3 Multidisciplinary orofacial pain care model
Table 25.3 Defining multidisciplinary and interdisciplinary care

Multidisciplinary care
Multiple providers from multiple disciplines
May, or may not, be coordinated between providers
Each provider has a clearly defined role but contributes individualized expertise in relative
isolation from one another
Generally care is coordinated by one provider
Interdisciplinary care
Providers from various differing specialties play complementary roles that, when integrated,
enhance patient care
Team members share responsibilities, problem solve as one, and share accountability
Planned or recommended treatments, therapeutic interventions, and other activities reflect the
team’s consensus view rather than the view of any single provider
288 S. McMahon
Fig. 25.4 Interdisciplinary
orofacial pain care model
Orofacial pain
Oral surgery
Primary care
Sleep Physical
medicine medicine &
rehab
Patient
Physical
therapy Neurology
Behavioral
Otolaryngology
health
Rheumatology
Interdisciplinary care, on the other hand, involves providers from various differ-
ing specialties that play complementary roles that when implemented together
enhance patient care (Fig. 25.4). In an interdisciplinary model, team members have
complementary roles and responsibilities, problem solving as one, and sharing
accountability for an overlapping continuity of care. Treatment decisions are con-
sensus based, and the process of arriving at a decision is essential to the team’s
recommendations and treatment implementation. Planned or recommended treat-
ments, therapeutic interventions, and other activities reflect the team’s consensus
view rather than the view of any single provider [5] (Table 25.3).
Although each clinician may have limited success in managing the “whole”
patient alone, the assumption behind a team approach is that it is vital to address
different aspects of the problem with different specialists in order to enhance the
overall potential for success. Although these programs provide a broader frame-
work for treating the whole complex patient, they have added another dimension to
the skills needed by the clinician: those of working as part of a coordinated team.
Failure to adequately integrate care may result in poor communication and distrust
among team members, fragmented care, and eventually confusion and failure in
the clinical management process. Team coordination can be facilitated by a well-
defined evaluation and management system that clearly integrates all team mem-
bers [6].
As previously discussed, the complex neurobiological, behavioral, and psycho-
social problems associated with most patients with orofacial disorders can best be
managed by an organized multimodal approach that integrates self-care and health
care. Patient education, self-responsibility, long-term change, and lasting doctor-

patient relationships must be emphasized from initial visit onward.
A prerequisite to implementing a team approach is an inclusive medical model
and conceptual framework that places the physical, behavioral, and psychosocial
aspects of illness on an equal and integrated basis. Although each clinician under-
stands a different part of the patient’s problem, he or she can integrate them with
other clinicians’ perspectives and see how each part is interrelated in the whole
patient. For example, a dentist or physician will evaluate poor postural habits, a psy-
chologist will evaluate emotional problems or social stressors, and together they may
address other variables such as sleep disturbance. Each factor will become part of the
problem list to be addressed in the treatment plan. In the process, the synergism of
each factor in the etiology of the disorder becomes apparent to clinicians (e.g., social
stressors lead to depression, depression leads to poor posture and muscle tension, and
the poor posture and muscle tension may lead to myalgia or myofascial pain).
Likewise, a reduction in each factor will work synergistically to improve the
whole problem. Treatment of only one factor may improve the problem, but relief
may be partial or temporary. Application of these concepts requires an interspe-
cialty collaboration of evaluation and management where the providers of health
care accept responsibility for addressing the multifaceted problems that exist.
The problem list for a patient with a specific chronic illness includes both a
physical diagnosis and a list of contributing factors. This broad understanding of the
patient is then used in a long-term management program that both treats the physi-
cal diagnosis and helps reduce these contributing factors.
The purpose of treatment includes four goals:
1. Alleviating symptoms
2. Improving functional capacity
3. Reducing negative effects of the illness on the patient’s lifestyle
4. Restoring the patients’ independence from the health-care system
Treatment of the physical problem includes the accepted dental, medical, physi-
cal, or surgical therapy for that diagnosis. Reduction of contributing factors is
accomplished through appropriate behavioral or psychological techniques such as
education, behavior modification, biofeedback, family therapy, and exercise. Patient
education of the pathophysiology of the pain condition can be a key tool in success-
ful treatment and is often overlooked in routine care.
Clinicians must rely on the patient and family self-responsibility for making
changes through a home program of self-care, and this begins with having a basic
understanding of how the pain condition is affecting them. Improved understanding
often equates to improved treatment adherence. Self-care facilitated in a supportive
environment in which the patient hears the same message from multiple clinicians
and gains the sustained insight, support, and care needed to make the changes that
both reduce the pain and improve health, and independent functioning also strength-
ens the prognosis.
290 S. McMahon
25.3 I mplementation of an Interdisciplinary Approach

to Orofacial Pain
Patients in both interdisciplinary and multidisciplinary systems may undergo three

phases of care: evaluation, management, and follow-up. A breakdown of each phase
is listed in Tables 25.4, 25.5, and 25.6:
25.3.1 Evaluation
A patient with a recurring problem presents to the clinic and is examined to deter-
mine the physical diagnosis and whether the patient can be helped by the team
approach. The clinician explains the diagnosis (if known), what diagnostic tests are
necessary, and how the team program can help the patient.
The clinician may explain [6]:
The symptoms you are experiencing are caused by (physical diagnosis). This diagnosis is
characterized by (signs, symptoms, and pathophysiology in lay terms). As you can see,
these characteristics fit your situation closely. However, in addition to the diagnosis, there
are other factors such as (direct contributing factors) that will lead to (physical diagnosis)
and need to be considered. These factors will (put strain on muscles or joints, irritate blood
vessels, nerves). We need to do (diagnostic and lab tests or consults) to confirm the diagno-
sis and other (behavioral, sleep) evaluations to evaluate other contributing factors. The
Table 25.4 Interdisciplinary evaluation

Initial comprehensive history/examination
Establish an initial diagnosis to determine if a team approach is applicable
Explain the diagnosis, additional tests if necessary, and how the team program can help the
patient
Complete informed consent to care if the patient desires treatment
Determine problem severity
Additional diagnostic testing
Special consultations
Thorough health and illness history
Listing of contributing factors
Evaluation by each of the team clinicians to establish a problem list
Chief complaint
Corresponding physical diagnoses
Contributing factors
Treatment planning conference: team members only
Discuss individualized and common findings
Establish a consensus on the diagnosis
Create an integrated, treatment plan designed to treat the diagnosis and reduce contributing
factors
Synthesis meeting: team members, patient, and family/significant others to:
Review the diagnosis and contributing factors
Explain the interrelationships of these factors
Assure mutual understanding
Present the individualized treatment plan
Table 25.5 Interdisciplinary management

Primary goals:
1. Reduction of symptoms and their negative effects
2. Return of normal function without need for future health care
Long-term individualized management program (with same team) that integrates:
Long-term patient education and training with each clinician
Review diagnoses and contributing factors
Discuss the need to change these factors
Educate on how to change
Short-term medical/dental care and behavioral and physical therapy
Physician or dentist
Physical diagnoses
Short-term care as indicated
Monitoring of treatment efficacy
Psychologist or behavioral therapist
Instruction about contributing factors
Diagnosing, managing, or referring for primary psychological disturbances
Establishing a program to support the patient and family in making changes
Physical therapist
Provides support, instruction, and management program (i.e., exercise regimen)
May also provide special care modalities (i.e., occupational therapy)
Ensure clear, concise, and ongoing communication (written and verbal) between the various
providers and with the patient
Typically involves a sequence of weekly to monthly visits for over 6 months
Table 25.6 Interdisciplinary follow-up

First, a brief follow-up synthesis meeting
Provide positive reinforcement of progress
Terminate the program (an option if treatment is complete or as otherwise indicated)
Provide a “diploma” with goals for maintaining improvement
Second, follow up sessions with one clinician to reinforce changes every 2–3 months
Changes are considered to be temporary unless they are sustained for over a year
If a sustained exacerbation of the problem occurs, the clinician and patient determine why
and decide if the team should resume efforts
Two common reasons for lack of symptom reduction are:
Incorrect or incomplete diagnosis
The presence of a diagnosis with pain that is intractable (i.e., continuous neuralgia)
Lack of compliance or ability to change a major contributing factor
In these situations, it is important to help prepare the patient for living with the pain, preferably
without addictive medications
Three goals:
Reduce effects of pain
Improve function
Achieve independence from the health-care system
Provide palliative relief with the use of an individualized home program:
Self-care: regular behavioral techniques and home care modalities
Pharmacotherapy
Complementary and alternative therapies
292 S. McMahon
treatment program is designed to reduce the (signs and symptoms) by treating the (diagno-
sis) and reducing these contributing factors. This is done by teaching you to (behavior
modification i.e., do exercises, change clenching), doing physical therapy to make muscles
and joints more comfortable, and asking you to wear a splint to protect and improve the
posture of the muscles and joints (if needed). In addition, we can help you get back to your
normal life style by helping to change (indirect contributing factors). Although we can do
some things, the majority of work is done by you, at home or work. It is a commitment and
it does take time. If you do the things necessary, you should expect to feel much better in as
little as 6 months. Although you still may have some pain, you usually will not notice it and
if you do, you will learn how to improve it on your own. Does this all makes sense to you?
What questions do you have? Do you want to participate in such a program?
If and when the patient desires management, evaluation can begin with diagnostic
tests or other consultations to confirm the diagnosis, determine health and illness
history, establish a contributing factor list, and utilize indices to measure problem
severity. This is followed by an evaluation session with each of team clinicians
(dentist and/or physician, psychologist, physical therapist, and other specialty pro-
viders as indicated) to assess the characteristics of the problem and establish the
patient’s unique problem list. The list includes the chief complaint, the correspond-
ing physical diagnoses, and a list of the contributing factors. The evaluation is fol-
lowed by a synthesis meeting (treatment planning conference), first among the team
members, and then with the patient and family or significant others to review diag-
nosis and contributing factors, explain the interrelationships of the factors, assure
mutual understanding, and present an integrated management program designed to
treat the diagnosis and reduce the contributing factors (Table 25.7). The purpose of
Table 25.7 Synthesis meetings (interdisciplinary treatment planning conferences) are designed
to enhance communication between clinicians, patient, and patient’s significant others
Synthesis meeting layout
Clinician synthesis
1. All clinicians included
2. Timing: 5–20 min
3. Establish a problem list and individual patient characteristics
4. Establish specific goals and priorities of treatment, prognosis, and potential problems
5. Determine individual clinician responsibilities in management program
Clinician-patient-family synthesis
1. All clinicians, patient, and significant others, in needed
2. Timing: 15–30 min
3. Dentist or physician reviews diagnoses, characteristics, and causal factors
4. Physical therapist reviews related behavioral and postural contributing factors, how they
related to physical diagnoses, and how to change them
5. Psychologist reviews behavioral and psychosocial contributing factors, how they related to
physical diagnoses, and how to change them
6. Review goals of improving symptoms by treating diagnoses and reducing contributing
factors
7. Each clinician describes his or her role in the overall program
8. Describe prerequisites to beginning program, guidelines of the program, and pragmatic
aspects
9. Verify patient understanding and desire to proceed
this meeting is to educate the family and to ensure consistent treatment planning and
communication among the clinicians, patient, and family [6].
25.3.2 Management Team
The patient then undergoes a long-term individualized management program (with

same team) that integrates long-term patient education and training with short-term
traditional medical or dental care. The primary goals of the program include reduc-
ing the symptoms and their negative effects while helping the patient return to nor-
mal function without need for future health care. The patient first participates in an
educational session with each clinician to learn about the diagnoses and contribut-
ing factors, why it is necessary to change these factors, and how to do it. The dentist
or physician is responsible for establishing the physical diagnoses, providing short-
term medical or dental care, and monitoring medication and patient progress. The
psychologist or behavioral therapist is responsible for providing instruction about
contributing factors, diagnosing, managing, or referring for primary psychological
disturbances, and establishing a program to support the patient and family in mak-
ing changes. The physical therapist is responsible for providing support, instruction,
and management program such as an exercise program. Depending on the thera-
pist’s background and the patient’s needs, this person may also provide special care
such as modalities or occupational therapy. Each clinician is also responsible for
establishing a trusting, supporting relationship with the patient while reaffirming
the self-care philosophy of the program, reinforcing change, and assuring compli-
ance. The patient is viewed as responsible for making the changes. The team meets
weekly to review current patient progress and discuss new patients.
25.3.3 Follow-Up
The management program typically involves a sequence of weekly to monthly

visits for over 6 months. At the end of the management phase, a brief follow-up
synthesis meeting is scheduled with the patient to provide positive reinforcement
of progress, terminate the program, and provide a “diploma” with goals for main-
taining improvement. This is followed by follow-up sessions with one clinician to
reinforce the changes every 2–3 months. The changes are considered to be tempo-
rary unless they are sustained for over a year. If a sustained exacerbation of the
problem occurs, the clinician and patient determine why and decide if the team
should resume efforts. Reasons for failing to achieve the four goals are many and
varied. Assuming the correct physical diagnoses, contributing factors, and treat-
ment plan, two common reasons for lack of symptom reduction are (1) the pres-
ence of a diagnosis with pain that is intractable, such as continuous neuralgia, and
(2) lack of compliance or ability to change a major contributing factor. In these
situations, it is important to help prepare the patient for living with the pain, pref-
erably without addictive medications. This can be facilitated by helping the
294 S. McMahon
patient achieve the other three goals (reduce effects of pain, improve function,
and achieve independence from the health-care system) and provide palliative
relief with the use of an individualized home program of self-care, regular behav-
ioral techniques, home care modalities, pharmacotherapy, and complementary
and alternative therapies as indicated.
25.3.4 Cost Control Using an Interdisciplinary Team
The interdisciplinary team approach is designed to address cost control factors. It

replaces high-cost dentist or physician care by using less costly health-care profes-
sionals, other support staff, and surveys to collect and tally repetitious patient infor-
mation; the dentist or physician is maintained as the health-care team manager. It
also focuses on education and self-responsibility in order to reduce care-seeking
behavior and dependency and help prevent the development of a perceived need for
extensive health care for other problems of living.
One of the major factors that lead a patient with a short-term problem into
developing a chronic pain syndrome is the lack of adequate recognition and treat-
ment of the whole problem during the first few months of pain. Thus, in order to
prevent development of a chronic pain syndrome, a patient needs to be managed
comprehensively from the beginning. Although individual clinicians can do this,
the time commitment and training required to provide dental or medical treat-
ment, teach exercises, and address contributing factors by one clinician are often
prohibitive, typically less effective, and ultimately frustrating for the solo clini-
cian. However, not all patients with pain require a team approach. Sometimes
singular treatments such as splints or biofeedback are effective alone. A decision
needs to be made at the initial evaluation on the need for a team or not. Criteria
for making this decision include factors such as long duration of pain, overuse of
medication, the presence of psychological or sleep disturbance, severity or extent
of comorbid chronic pain conditions, potential for secondary gain, gross confu-
sion, and significant parafunctional habits. The use of an interdisciplinary, biopsy-
chosocial-derived patient intake form can readily elicit the degree of complexity
of a case at initial evaluation.
Potential barriers to implementing this evaluation and management system in
clinical practice may include dentists’ or physicians’ reluctance or inability to deal
with behavioral and psychosocial aspects of illnesses, hesitation to add a team
approach to their busy individual practices, or lack of motivation to integrate a
self-care philosophy to their concepts of disease management. However, the great-
est effort involves the implementation of the system (finding the right clinicians,
preparing them for working in a team, rearranging schedules, etc.). Once the sys-
tem is up and running, however, each clinician enjoys the benefits of collegial
support, shared patient care, and team comradery. Each learns from the other clini-
cians and is therefore better able to recognize contributing factors. This system’s
simplicity, potential office and patient cost-effectiveness, combined use of tradi-
tional dental and medical care, and its easily duplicated information system facili-
tate its replicability and adaptability. The interdisciplinary team model, in the
opinion of many clinicians, researchers, and educators, may be the most effective
management option.
25.4 I mplementation of an Multidisciplinary Approach

to Orofacial Pain
It is important to realize, however, that interdisciplinary management does not

necessarily mandate that a patient must be assessed and treated by multiple pro-
fessionals. There are many situations where it is simply not possible, usually due
to a lack of resources, location, or availability, to provide truly integrated interdis-
ciplinary care. In these situations individual provider who possesses a broad array
of skills may be in the best position to deliver optimum orofacial pain manage-
ment. Such skills are based upon an expanded understanding of orofacial pain that
appreciates the unique anatomic and physiological complexities of cranial nerve
systems and incorporates recent advances in the neurobiology of pain.
Contemporary neuroscience validates the need for an interdisciplinary approach
toward orofacial disorder practice. It moves the provider beyond a simple biome-
chanical or inflammatory concept of pain, substantiates the biologic basis for the
biopsychosocial model of pain, and provides pathophysiologic links between oro-
facial pain disorders and common comorbid pain conditions such as irritable
bowel or fibromyalgia.
Multidisciplinary orofacial pain management also consists of the three basic
phases: evaluation, management, and follow-up.
25.4.1 Evaluation
Similar to the interdisciplinary method, multidisciplinary care begins with a com-

prehensive patient history conducted by an individual provider. Perhaps the most
expeditious way to obtain such a history is via a detailed patient questionnaire. Such
an instrument seeks not just information about the chief complaint but also records
a complete medical and treatment history, asks about any site of pain anywhere in
the body, assesses affect, checks for awareness of muscle parafunction, reviews
personal habits and nutrition, seeks insight into vocational and family concerns,
inquires about negative life events (i.e., abuse, assault, childhood neglect, etc.), and
296 S. McMahon
Table 25.8 Multidisciplinary evaluation

Patient completes a comprehensive, detailed, patient questionnaire that is reviewed by the
patient and provider
Discuss history of the chief complaint
Complete medical and treatment history
Ask about any site of pain anywhere in the body
Review personal habits and nutrition
Check for awareness of muscle parafunction
Assess affect (stress, anxiety, depression, anger, etc.)
Vocational and family concerns
Negative life events (i.e., abuse, assault, childhood neglect, etc.)
Solicit information about sleep
Initial comprehensive examination
Complete oral, head, and neck examination
Distinguish sites from sources of pain
Determine the extent of physical dysfunction
Integrate appropriate imaging, diagnostic testing, and/or laboratory studies
Establish a list of differential diagnoses and contributing factors
Explain the etiology and pathophysiology and thoroughly discuss all treatment options and
prognosis
Complete informed consent to care if the patient desires treatment
solicits information about sleep. After a detailed history is obtained, comprehensive

head, neck, and oral examinations are completed. These exams should distinguish
the sites from sources of pain and the extent of physical dysfunction and should also
integrate appropriate imaging and/or laboratory studies. The information collected
from each step is the foundation for establishing a list of differential diagnoses and
contributing factors [1] (Table 25.8).
25.4.2 Management
In some cases, the provider may have the appropriate training, experience, and
resources to handle all of the patient’s treatment needs and address the relevant
contributory factors. In other instances, the assistance of additional practitioners
may be required. Health-care providers often involved with the global management
of orofacial pain patients include dentists, oral surgeons, primary care physicians,
neurologists, physiatrists, physical therapists, psychiatrists, psychologists, otolaryn-
gologists, and rheumatologists (Table 25.9).
Table 25.9 Management
Primary goals:
Reduction of symptoms and their negative effects
Return of normal function without need for future health care
In some cases, the provider may have the appropriate training, experience, and resources to
handle all of the patient’s treatment needs and address the relevant contributory factors
Consider the impact of all sources of pain, including those outside the orofacial region
Non-trigeminal sources of nociception may:
Refer pain cephalad
Facilitate cranial nerve-mediated muscle parafunction
Induce co-contraction and disrupt sleep
Reduce masticatory and cervical muscle overuse to decrease fatigue, pain, and joint
overloading
Employ behavioral strategies that increase parafunctional awareness and diminish the
brain activity that may facilitate inappropriate muscle use [7]
Reduce physiological arousal
Use relaxation techniques, such as diaphragmatic breathing and imagery, to affect brain
regions that may adversely influence pain thresholds, muscle activity, or sleep
Recognize the need to address negative affect, stressful personal-family-vocational issues,
and the excessive use of stimulants (caffeine, nicotine, etc.)
Enhance sleep
Explore all factors that can delay, disrupt, or lighten sleep
Educate patients about the importance of sleep hygiene measures and cognitive behavioral
strategies such as sleep restriction, stimulus control, and relaxation techniques [8]
When prescribing sedative-hypnotic medications, give preference to those that promote the
later stages of sleep
In other instances, the assistance of additional practitioners may be required
Health-care providers often involved with the global management of orofacial pain patients
include:
Dentist specialists
Primary (or internal) care medicine
Behavioral health
Neurology
Otolaryngology
Rheumatology
Physical medicine and rehabilitation/physiatry
Physical therapy
Sleep medicine
Ensure clear, concise, and ongoing communication (written and verbal) between the various
providers and with the patient
Typically involves a sequence of weekly to monthly visits for over 6 months (based on
individual treatment needs)
25.4.3 Follow-Up
Essentially the same as with the interdisciplinary plan, however, additional consul-
tation from another provider (as discussed above) may be indicated (Table 25.10).
298 S. McMahon
Table 25.10 Follow-up
First, a brief follow-up(s)
Ensure efficacy of treatment
Establish adherence to the treatment plan
Provide positive reinforcement of progress
Adjust/coordinate care as indicated
Second, follow up sessions to reinforce changes every 3–6 months
Changes are considered to be temporary unless they are sustained for over a year
If a sustained exacerbation of the problem occurs, the clinician and patient determine why
and decide if they should resume efforts (or seek additional consultation)
Two common reasons for lack of symptom reduction are:
Incorrect or incomplete diagnosis
The presence of a diagnosis with pain that is intractable (i.e., continuous neuralgia)
Lack of compliance or ability to change a major contributing factor
In these situations, it is important to help prepare the patient for living with the pain, preferably
without addictive medications
Three goals:
Reduce effects of pain
Improve function
Achieve independence from the health-care system
Provide palliative relief with the use of an individualized home program:
Self-care
Regular behavioral techniques
Home care modalities
Pharmacotherapy
Complementary and alternative therapies
25.5 N
eurobiological Considerations in Orofacial Pain
Management
One of the difficulties in dealing with orofacial pain complaints relates to the struc-
tural complexity of the trigeminal nerve system. It is incumbent for clinicians to
distinguish true sources of pain from trigeminal sites of pain and to discern the loca-
tions of all non-trigeminal sources of pain. The trigeminal sensory nuclei receive
extensive input from structures within the brain stem and midbrain that process sen-
sory information from tissues outside the face. The trigeminal interpolaris and spinal
tract nuclei receive convergent sensory input from the facial, glossopharyngeal, and
vagus nerves, as well as the upper cervical nerves (C1–C4) [9]. Convergent nocicep-
tive input from non-trigeminal afferent neurons provides an anatomic explanation as
to how disorders in remote regions of the head and neck may refer pain to the face.
Another important consideration in orofacial pain is the capability of non-
trigeminal brain centers to induce non-volitional trigeminal motor responses, mus-
cle activity that has been often labeled as “parafunction.” Integrative centers within
the brain stem, such as the parvocellular reticular formation and paratrigeminal
nucleus, receive both noxious and non-noxious visceral, cutaneous, and autonomic
input and, via connections with the trigeminal nuclear complex, may produce a
masticatory muscle response [10]. Similarly, activity in higher brain centers, such as
the limbic system and prefrontal cortex, can engage descending neural circuits also
capable of inciting masticatory muscle activity [11]. Concurrent with induced mas-
ticatory responses, hypoglossal, spinal accessory, facial, glossopharyngeal, and
vagal motor centers may also be activated. Afferent input from tissues controlled by
these nerves may contribute to the wide constellation of symptoms seen in wide-
spread pain cases with multiple comorbidities.
Persistent, nonfunctional masticatory muscle activity may have significant bio-
logic and clinical consequences. Even low levels of muscle activity excite metabore-
ceptors that send impulses to the central nervous system via group III and IV afferents
(A delta and C fibers) [12], the same classes of first-order neurons activated by
peripheral nociceptors. Metaboreceptor activity of sufficient intensity and duration
may be noxious and produce pain. Excessive metaboreceptor activity may lead to
central sensitization, facilitate the referred pain phenomenon associated with myo-
fascial pain, and induce masticatory muscle co-contraction. Activation may also con-
tribute to pathologic changes within the temporomandibular joint (TMJ). Prolonged
periods of increased intra-articular pressure have been associated with local tissue
hypoxia, free radical formation, and oxygen reperfusion injury, all factors thought to
play a role in the genesis of TMJ osteoarthritis and disc displacements [13, 14].
Interestingly, the presence of muscle pain may also decrease proprioceptive
feedback; thus, a patient may not be fully aware of the extent of their muscle para-
function or overuse [15]. There is an increasing body of evidence that many orofa-
cial pain patients frequently possess other remarkable physical and mental health
concerns. Turp and colleagues found that 82% of facial pain patients also had addi-
tional pain complaints outside the distribution of the trigeminal system [16]. Based
on an anonymous self-report survey, 68% of patients referred to a university orofa-
cial pain center indicated a history of physical or sexual abuse [17].
Recent investigations have shown that patients with temporomandibular disor-
ders often have coexisting conditions including irritable bowel disease, fibromyal-
gia, migraine, panic disorder, and others [18]. The link between these seemingly
disparate disorders is the potential of a shared neuropathophysiology involving
alterations in hypothalamic-pituitary-adrenal axis, autonomic nervous system, and
limbic system-prefrontal cortex responses [19]. Hyperactivity, hypoactivity, or lack
of coordination within or between the aforementioned systems could lead to dys-
functional allostasis, changes in vasomotor responses, modification in respiration,
and alterations in sensory processing [20].
In summary, when one considers the negative impact of these comorbid chronic
pain conditions, an integrated treatment approach, whether interdisciplinary or mul-
tidisciplinary, is vital to the successful management of orofacial pain conditions.
Disclosure Statement by the Author The opinions or assertions contained herein are the private
ones of the author(s) and are not to be construed as official or reflecting the view of the DoD or the
USUHS. The author does not have any financial interest in the companies whose materials are
discussed in this article.
300 S. McMahon
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Transformative Care for Orofacial
Disorders 26
James R. Fricton
Pearls of Wisdom
• When implementing transformative care for orofacial disorders, our main
goals should go beyond management and include training to reduce risk
factors and enhance protective factors and education on prevention toward
recurrence or toward a chronic pain state.
• Transformative care involves the following tasks:
1. Evaluating the person with chronic pain as a whole by identifying and
understanding both their risk and protective factors.
2. Improving the safety of treatments to minimize the development or pro-
gression of orofacial disorders as an adverse event.
3. Implementing a transformative model of healthcare through a team
approach
4. Continuing medical and dental education courses that review the funda-
mentals of this new approach to care. New healthcare routines should
include toolkits to implement online self-management training with
evidence-based therapies.
5. Supporting resources to help implement transformative care.
J.R. Fricton, DDS, MS

Schools of Dentistry, Medicine and Public Health, University of Minnesota and
HealthPartners Institute, Minneapolis, MN, USA
e-mail: frict001@umn.edu

DOI 10.1007/978-3-319-51508-3_26
302 J.R. Fricton
Table 26.1 Common orofacial disorders that require special diagnostic and treatment needs with
estimated prevalence
Orofacial pain disorders Estimated prevalence
Temporomandibular disorders 5–7%
Orofacial pain disorders (burning mouth, neuropathic, atypical pain, 2–3%
neurovascular)
Headache disorder (tension-type headaches, migraine, mixed, cluster) 20%
Orofacial sleep disorders (e.g., sleep apnea, snoring) 3–4%
Neurosensory and chemosensory disorders (e.g., taste, paresthesias, 0.1%
numbness)
Oromotor disorders (e.g., oral habits, occlusal dysesthesias, dystonias, 4%
dyskinesias)
Oral lesions (herpes, aphthous, precancer, cancer) 3–5%
Oral mucosal disease (e.g., lichen planus, candida) 1–2%
Dry mouth, salivary disorders, and xerostomia related to caries 2%
Oral systemic disorders (e.g., autoimmune, cancer, heart disease, etc.) 2–3%
Total estimated prevalence in general population 42–50%
26.1 Introduction
Orofacial disorders are among the most common conditions and include headache,
temporomandibular pain, orofacial pain, obstructive sleep apnea/snoring, dry
mouth, and many other conditions in the mouth, face, head, and neck with a collec-
tive prevalence of at least 40% of the population (Table 26.1) [1–5]. Because oral
and facial structures have close associations with functions of eating, communica-
tion, sight, and hearing as well as form the basis for appearance, self-esteem, and
personal expression, persistent pain or disease in this area can deeply affect an indi-
vidual both psychologically and systemically. A national poll found more adults
working full-time miss work from head and face pain than any other site of pain [6].
Unfortunately, access to care for patients with these disorders is often difficult
because the limited number of dentists and physicians who specialize in this area
and the fact that they care lies between medicine and dentistry. This book presents
a brief summary of the treatment needed for each type of orofacial disorders.
However, to best care for these disorders, this chapter describes a transformative
approach to care that has more success long term by shifting the paradigms of care
to be more patient centered with integration of patient training with treatment of the
condition.
26.2 The Problem with Orofacial Disorders
With at least 100 million US adults suffering from orofacial disorders, it has also
become a primary reason for seeking healthcare. Over half of all healthcare visits
are attributed to some type of pain condition, with pain from orofacial disorders
including headache, temporomandibular disorder pain, facial pain, and mouth pain
being the most common [1–4]. Since most health professionals including
26 Transformative Care for Orofacial Disorders 303
physicians and dentists are not trained in orofacial disorders, patients often shop
around seeing an array of medical and dental primary care and specialists and can
end up on trials of different medications, therapies, surgeries, and other treatments.
Yet, a survey of 405 health professionals found that 95% would like to refer these
patients to a specialist because of their complex nature [5, 6]. Because the special-
ties of orofacial pain and oral medicine are just emerging, there are insufficient
numbers of specialists in the field to provide adequate access to care for these prob-
lems. If pain continues, care may escalate to higher cost, higher-risk passive inter-
ventions such as ongoing opioid analgesics, polypharmacy, implantable devices,
injections, and surgeries [1–3, 14–19]. If opioid analgesics are used, especially at
high doses, there is an increased risk of abuse leading to unintended overdose-
related deaths, which now outnumber motor vehicle-related deaths in some states
[5–11]. Unfortunately, many people with pain after 1 month still have persistent
pain 5 years later despite these extensive interventions [16, 17].
This delayed recovery and progress of pain has less to do with failed treatment
than it is due to the presence of multiple risk factors that contribute to persistence of
the conditions. Although genetic factors may predispose one to chronic pain, there
is also much research which suggests that repetitive strain, depression, poor sleep,
stress, maladaptive postures, and ergonomics are among the many contributing fac-
tors leading to delayed recovery, failed treatment, and continued pain [12–23].
Despite recognition that many of these factors can be improved with self-manage-
ment strategies, they are often not addressed in routine care, which can lead to pain
persisting for years. Thus, pain becomes a problem when practitioners fail to engage,
empower, and educate patients in reducing risk factors and enhancing protective
factors to help prevent pain from becoming chronic [20–24]. Prevalence and impact
data as well as recommendations from the Institute of Medicine Report and the
National Pain Strategy show that more effort is needed in prevention and successful
early intervention using a transformative care approach when caring for patients
with pain conditions [22, 23]. If health professionals want to improve patient out-
comes, they need to consider helping people identify and change the multidimen-
sional risk factors that may contribute to delayed recovery and chronic pain. We can
only do this by shifting our care model from a provider-centric passive care model
to an active patient-centered transformative care model that educates, engages, and
empowers patients to transform their lives from one of pain and suffering to one of
health and well-being.
26.3 Transforming Pain to Health and Well-Being
A new approach that conceptualizes these conditions more broadly with a focus on
prevention and early intervention is recommended [32–35]. A human systems
approach provides a broader understanding of the role of diverse personal risk fac-
tors which can delay healing and perpetuate pain and dysfunction through recursive
feedback cycles that increase both peripheral and central sensitization [34–39]. A
transformative care model is the clinical application of a human systems approach;
304 J.R. Fricton
it integrates risk factor assessments and robust personalized self-management train-

ing of patients, integrated with evidence-based treatments [34]. Risk factor assess-
ment identifies both risk and protective factors that tilt the balance between pain and
suffering to health and well-being. Self-management programs can then help train
patients to reduce the identified risk factors, enhance protective factors, and reverse
the perpetuation of chronic pain. This can best be implemented through an integra-
tive team approach that supports the patient in implementing lifestyle changes and
long-term improvement in preventing chronic pain.
Transformation of our care to a broader conceptual model of care with new clini-
cal paradigms can be challenging even for the most innovative healthcare profes-
sional. For this reason, additional training is recommended. One example of a
resource for transformative care are toolkits (www.preventingchronicpain.org)
intended for health professionals to integrate online self-management training along
with evidence-based treatments as part of routine care. In addition, the massive open
online course (MOOC) on preventing chronic pain (www.coursera.org/learn/
chronic-pain) presents an online continuing education course for health profession-
als to review the fundamentals of this new approach to care [40, 41]. This chapter
briefly discusses this new approach to care.
26.3.1 Human Systems Model
This human systems conceptual model assumes that people are complex, multi-
dimensional, and dynamic and live within an ever-changing social and physical
environment. In contrast, the traditional biomedical model is based on a scien-
tific paradigm that is unidimensional, reductionist, and inflexible, based primar-
ily on understanding underlying pathophysiology (Table 26.2). Healthcare
professionals often tend to see what they treat and treat what they see. If they see
only the pathophysiology, the complex set of risk and protective factors in
chronic pain will be missed. As a result, success of treatment can be compro-
mised by limited approaches that only address part of the problem. For example,
some systematic reviews of biomedical treatments for chronic pain have found
that even with the most efficacious treatments, the improvement occurs only
slightly above placebo [28–30].
A broader conceptual basis is required for orofacial disorders, one that includes
understanding how different realms of our lives can interact and contribute to
chronic pain. Human systems theory (HST) stems from research in general systems
theory and originated in ecology out of the need to explain the interrelatedness of
organisms in ecosystems [33–40]. A human systems approach integrates concepts—
neuroplasticity, mind-body connectedness, positive psychology, cybernetics, chaos
theory, social psychology, cognitive behavioral science, and mindfulness—to help
explain the delicate balance between health and illness (Table 26.3) [33–40]. While
many distinct pathophysiological mechanisms may occur in chronic pain condi-
tions, HST suggests that it is the complex interaction of diverse factors below, which
can initiate, perpetuate, or even protect people from the chronic pain progression
Table 26.2 Comparison of the traditional biomedical model and a human systems model
Concept Biomedical model Human systems model
Conceptual Reductionist, mechanistic, Holistic, fluid, flexible
basis inflexible
Application of Relies on objective physical Relies on objective and subjective
scientific measures, single brief measures, multiple interventions over
methods interventions, and randomized longer periods, and pragmatic clinical
controlled trials trials
Etiology Pathophysiologic etiology based Multifactorial dynamic etiology of
on single static etiology (e.g., chronic illness (e.g., influence of risk and
infectious agent, structural protective factors on physical tissues)
change, cancer)
Problem list Identify chief complaint and Identify chief complaints, diagnoses,
diagnoses in the physical or along with contributing factors in each
psychiatric realm aspect of life—body, mind, spirit,
lifestyle, emotions, environment, and
society
Treatment Unidimensional—encourages Multidimensional—integrates multiple
strategy single sequential treatments interventions with self-management of
risk and protective factors
Providers Single clinician providing single Interdisciplinary, integrative team of
intervention that is easy to clinicians who address multiple levels of
implement. May lead to contributing factors. More complex to
fragmented approaches implement
Reimbursement Well supported by traditional Supported by evolving healthcare
healthcare delivery system with delivery system with economic incentives
an economic model that rewards for patient-centered care
procedures over process
Outcomes Good outcomes with acute Good outcomes with chronic illness due
conditions; poor outcomes with to use of transformative care model with
chronic illness due fragmentation self-management, biomedical
of multiple single treatments interventions, and a team approach
Table 26.3 Human systems theory provides an inclusive conceptual framework for transforma-
tive care and integrates multiple theories
Systems theory and See the big All realms of an ecosystem are interrelated and
ecology picture impact each other
Neuroplasticity and The brain can We can learn to turn the volume up and down on
mind-body change pain pain with changes that influence peripheral and
connections central sensitization
Positive psychology Positive wins Strengthening protective factors, cultivating
over negative strengths, and encouraging what is best within a
person have more impact than reducing the negative
Cybernetics What goes Each element of a system generates a change, which
around comes causes positive or negative feedback to the entire
around system and leads to first-order reactive change,
second-order revelation change, or third-order
transformative change
(continued)
306 J.R. Fricton
Chaos theory It’s the little Small differences in initial conditions may yield
things every day widely diverging outcomes within dynamic systems
that matter like humans. Thus, the influence of multiple small
risk and protective factors can play a significant role
in shifting the balance between health and illness
Social psychology Relationships Our thoughts, feelings, and behaviors are influenced
matter to our by the actual, imagined, or implied presence of
health others
Cognitive behavioral We are what we How we think (cognition), how we feel (emotions),
science repeatedly think, and how we act (behavior) all interact and can
do, and feel influence each other
Mindfulness Be here now By training our minds to be in the present moment
and nonjudgmental, our health and well-being are
enhanced
Table 26.4 Description of the seven realms (with the acronym BLESS ME) in human systems
approach to preventing chronic pain
Realm Description Protective factors Risk factors
Body Physical and Balanced relaxed posture, Genetic risk, comorbid conditions,
physiologic stretching, strengthening, poor posture, tight weak muscles,
aspects of the and conditioning exercise hypo- or hypermobile joints, poor
body conditioning, and injury
Lifestyle Lifestyles and Protective diet, steady Poor diet, sedentary life, prolonged
behaviors that pacing, being active, regular sitting, poor sleep, hurrying/
we do sleep, low-risk behaviors, rushed, repetitive strain, high-risk
regularly high energy, and compliance behaviors, chemical use, low
with protective actions energy
Emotions Positive and Sustained positive emotions, Prolonged negative emotional
negative such as joy, excitement, experiences, anger, anxiety,
feelings we confidence, optimism, sadness, fear, and depression
experience happiness, and contentment
Society Social Positive relationships, social Poor relationships, conflict, abuse,
relationships support, helping others, posttraumatic stress, low social
with the reward for recovery, e.g., support, isolation, secondary and
people around family, friends, colleagues, tertiary gain
us community, society
Spirit Higher beliefs Purpose, direction, beliefs, Stress, burnout, disbelief,
and purposes faith, hope, self-compassion, cynicism, doubt, helpless, and
that drive us and self-esteem hopelessness
Mind Thoughts and Whole understanding, Ignorance of problem, low
attitudes resilience, self-efficacy, resilience, low self-efficacy/
self-control, accepting control, refuse responsibility, poor
responsibility, realistic compliance, unrealistic
expectations, and engaging expectations, and passive coping
in active coping
Environment Physical Clean, organized, safe Living within an unclean, chaotic,
environment environment, and an and disorganized environment
that approach that is protective, with activities that are negligent,
surrounds us cautious, and careful dangerous, risky, and increase risk
of injury, accident, and trauma
and peripheral to central sensitization. HST views a person as a whole, with the
interrelationship between different realms of their life contributing to this balance
(Table 26.4). These realms are not static and independent but rather are dynamic,
evolving, and interrelated processes that involve sets of risk and protective factors
that can shift the balance between health and illness.
Successful management of orofacial disorders includes preventing the progres-
sion from acute pain to chronic or even intractable pain. An illness such as a pain
disorder often begins with initiating factors such as an acute physical injury. In
most cases, this condition is transient and heals without complication or persis-
tence. However, if a sufficient, even small, number of risk factors are present, it
can shift the balance from the healing of acute pain to a delayed recovery and
chronic pain. Strengthening protective factors and successful reduction of multiple
risk factors in the cycle may have the significant impact in healing the injured tis-
sues. This strategy supports the concepts of multimodal and interdisciplinary team
care that amplifies the small effect of interventions by including self-management
training to achieve the best possible outcomes. To achieve these outcomes, several
new strategies are needed by the healthcare provider including recognizing their
role as agent of change, employing an inclusive problem list (see below), deter-
mining the complexity of patient, following a decision tree for increasing the
potential for successful management, and employing interdisciplinary and inte-
grated treatment protocols to address the whole problem list. When evidence-based
biomedical treatments are combined with robust patient training to reduce risk
factors and enhance protective factors, the potential of transforming a person’s life
from one of illness to health and wellness is enhanced. This premise is the basis for
a transformative model of pain care.
26.3.2 Transformative Care
The Institute of Medicine’s (IOM) monograph, Relieving Pain in America, empha-

sizes the need to transform our current passive model of doctor-centered care into
one that is patient centered [1]. The document states, “Healthcare provider organi-
zations should take the lead in developing educational approaches and materials
for people with pain and their families that promote and enable self-management.”
The IOM further states that health professionals’ primary role in caring for chronic
pain requires guiding, coaching, and assisting patients with day-to-day self-man-
agement in addition to evidence-based biomedical treatments [22]. Unfortunately,
most health professionals lack the time and training to perform this role and find
little support and reimbursement from health plans for doing so. Transformative
care is a new care model that integrates robust self-management training with the
best and safest evidence-based treatments. Clinical trials of self-management strat-
egies that activate the patient through exercise and cognitive and behavioral
changes have equal or better efficacy than passive treatments in preventing or alle-
viating chronic pain [24–33]. When self-management training supplements treat-
ments, the long-term outcomes can be dramatically improved while also reducing
308 J.R. Fricton
Table 26.5 Clinical paradigms associated with transformative care and a human systems
approach to preventing chronic pain
New paradigm Statement that shifts to the new paradigm
Understand the whole Identify all diagnoses, risk factors, and protective factors in the seven
patient realms of life (body, mind, spirit, lifestyle, emotion, social, and
physical environment) to shift the balance from illness to health
Each patient is complex Multiple conditions and interrelated contributing factors may initiate,
result from, increase risk, or decrease risk of illness. Each needs to be
addressed as part of management strategy
Self-responsibility is You have more influence on the problem than any treatment
key to recovery provided. Will you take ownership and control of the condition?
Self-care You will need to make daily changes in order to improve your
condition
Education and training We will teach you how to make these changes
Long-term change Change only occurs over time, and it may take months for the
changes to have a large impact on reducing pain and symptoms
Strong provider-patient We, as health professionals, will support you as you make the
partnerships changes. We can be an agent to help you change
Personal motivation Will you be able to make the changes needed?
Social support You may need help to make these changes
Change process Change will occur incrementally over time
Fluctuation of progress Expect ups and downs during the recovery process
the patient’s dependency on the healthcare system. Thus, a transformative care

model can help transform not only the patient’s life but the healthcare system too.
The clinical application of transformative care involves identifying and reduc-
ing risk factors for chronic pain while also training the patients in improving pro-
tective factors, as illustrated in Table 26.4. Transformative care includes the use of
pain risk assessments to identify risk and protective factors as part of a whole
person problem list. Personalized care strategies include integrative teams that can
be supported by health coaches, social support networks, and consumer-based
health information technology for both patient training and documenting out-
comes. Since patients often expect to have a passive role in care, these new para-
digms need to be conveyed to the patient as part of the evaluation (Table 26.5).
Embracing patient-centered healthcare paradigms such as self-responsibility, edu-
cation, personal motivation, self-efficacy, social support, strong provider-patient
relationships, and long-term change will shift the balance of care from one of a
passive, dependent patient to an empowered, engaged, and educated patient
[22, 23]. Ultimately, this paradigm shift has potential to not only improve the qual-
ity of care and enhance pain and functional outcomes but also will significantly
reduce healthcare costs. In the process, the Institute for Healthcare Improvement’s
triple aim of improving population health, enhancing the patient care experience
(including quality, access, and reliability), and controlling or reducing cost of care
will be achieved [44].
Table 26.6 Health consciousness

Fifth level Transformative health consciousness
Wellness warriors live each day with maximum implementation of health and
wellness actions in all seven realms and actively act as evolutionary co-creators to
help others achieve the same
Fourth Enlightened health consciousness
level Health actives live each day mindful of the knowledge and decisions that
determine their own health and well-being in all seven realms and take active steps
to maintain it
Third level Informed health consciousness
Weekend actives are informed of the importance of health and well-being and take
some time each week to practice healthy actions in some realms but are not able to
maintain this most days or in all realms
Second Illness-centered health consciousness
level Illness-centered passives react to illnesses and take only limited short-term actions
to help recover from the illness but often do not sustain the changes over time
First level Medically dependent health consciousness
Medically dependent passives are continuously involved in passive treatment with
a health professional and take little to no time and effort to take responsibility and
actions to help their own health and well-being
A person’s level of health and wellness consciousness determines the degree to which they take
actions to maintain their optimal health and wellness and determines the amount of healthcare they
require. The higher levels of health consciousness requires less healthcare than lower levels
26.3.3 The Healthcare Provider as an Agent of Transformative

Change
Health professionals need to recognize their important role of not only providing
treatments but also helping the people transform their health consciousness from
being illness centered and healthcare dependent to one of maintaining health and
well-being on a daily basis (Table 26.6). As part of this, health professionals need to
recognize the limits of biomedical treatments such as medication, interventions, and
surgery that may in some cases lead to additional problems, like adverse events,
addictions, neuropathic pain, fibrosis from repeated surgeries, and secondary gain
from care seeking to validate their illnesses. Rebound pain from medications can actu-
ally be part of the patient’s pattern of problems and generate self-sustaining chronic
pain. If clinicians understand their integral role in tipping the balance from illness to
health, they can be an agent of transformative change and part of the long-term solu-
tion. They can help patients reconstruct their world into one of health and well-being
and not illness. Clinicians can facilitate patients achieving the deepest most perma-
nent order of change—a third-order change, defined as the capacity to change their
epistemology of health and illness, i.e., how they understand of their own powerful
role in developing illness, thereby learning how they can maintain health and well-
being for their lifetime. Through this third order of change, patients may see their
world differently as enlightened and transformative wellness warriors. To do so, they
first must understand each component of the problem by establishing a complete
problem list that includes both the physical problem and the contributing factors.
310 J.R. Fricton
26.3.4 Determine the Complete Problem List
Human systems theory expands the traditional “problem list” of the chief com-
plaint and physical diagnosis to also include the list of contributing factors in
each of the seven realms—mind, body, emotions, spirit, lifestyle, social, and
physical environment. The physical diagnosis defines the physical problem
that is responsible for the chief complaint and associated symptoms, whereas,
contributing factors include those factors that initiate, perpetuate, or result
from the disorder but in some way complicate the whole problem.
Multidimensional assessment will help determine which contributing factors
are present. Specific risk factors for chronic pain are included in Table 26.4 and
may range from peripheral factors such as repetitive stress-strain and postural
habits to central mediating factors such as anxiety and depression, comorbid
conditions, somatization, and catastrophizing [44, 45–49]. Protective factors—
level of coping, self-efficacy, exercise, and patient beliefs such as perceived
control over pain and understanding that pain is a sign of strain or injury—
reduce vulnerability to chronic pain [40, 41]. Social support can also affect
outcomes.
26.3.5 Matching Complexity of the Patient with the Complexity

of Care
The level of care for patients can vary considerably from simple to complex.
Patients with complex chronic illness often present with a frustrating medical
and dental situation, which may include persistent aggravation of symptoms,
multiple clinicians, long-term medications, repeated healthcare visits, and an
ongoing dependency on the healthcare system. Thus, successful management is
enhanced if the level of complexity is determined and matched to the complex-
ity of the treatment strategy. Singular treatment strategies such as self-manage-
ment, physical therapy, or medication can be quite successful with patients with
few contributing factors but often fail in patients with complex contributing
factors, due to the chronic nature of the disease and the long-standing maladap-
tive behaviors, attitudes, and lifestyles. Thus, it is helpful to follow a decision-
making process that can distinguish simple from complex patients and direct the
treatment strategy.
Figure 26.1 outlines the decision tree for sequencing evaluation and management
for simple and complex cases. Once the complete problem list is developed, it can be
used as criteria to distinguish simple and complex patients. Complexity of the patient
increases with the presence of multiple diagnoses, persistent pain longer than
6 months, significant emotional problems, frequent use of healthcare services or
History and
examination
1. Chief complaints
2. Physical diagnosis
1. Determine 3. Risk factors
problem list 4. Protective factors
Simple Complex
3. Treat or use 2. Simple or 4. Treat now or

self care only? complex? later?
Single clinician
Team of clinicians
Fig. 26.1 A decision tree for triaging patients and enhancing outcomes and successful care
medication, repetitive muscle strain, and significant lifestyle disturbances. In addition,

there are some complex patients who warrant deferral of treatment until more com-
plex problems are addressed. The criteria for not treating until these problems are
resolved include primary chemical dependency, primary psychiatric disorder, signifi-
cant litigation, and a patient unmotivated and/or overwhelmed with other concerns.
26.3.6 Integrative Care
Multimodal treatments within an interdisciplinary integrative care model can best

set the stage for a second or third level change in the patient’s life by addressing the
physical diagnosis and all of its contributing factors. This model includes screening
for pain risk assessment; implementing cognitive, emotional, and behavioral
change; self-management; patient advocacy; and focus on a patient-centered model.
Once complexity is determined, simple chronic illness patients can be successfully
treated using a single clinician and treatment to achieve resolution in 2–3 months.
With more complex cases, it is recommended they be managed by an integrative
team of clinicians to achieve the best level of improvement in the pain condition
typically achieved in 3–6 months. Integrative care is the practical application of this
model in clinical practice by combining the practices and care strategies of a team.
Different aspects of the problem can be addressed by different health professionals,
312 J.R. Fricton
often including physicians, dentists, health psychologists, and physical therapists,

as appropriate, along with pain coaches, in order to enhance the overall potential for
success. A pain coach may be an excellent addition to a busy primary care or spe-
cialty practice to help guide and support the patient in achieving their goals of
reducing pain and its interference in life activities through learning self-management
strategies. Teams can be interdisciplinary (one setting) or multidisciplinary (multi-
ple settings). The use of a team helps to understand and manage the whole patient,
allows work on multiple aspects of the problem simultaneously, improves patient
compliance and outcome, saves time, and is more economical and more enjoyable
as the team works together. A consistent philosophy and message to the patient are
needed including the importance of self-care, self-responsibility, and education
using concepts of the human systems approach and the transformative care model.
Success is dependent upon communication and integration among clinicians and
proper patient selection.
Conclusion
There are several areas of focus for health professionals in implementing trans-
formative care and managing and preventing chronic pain. These include:
1. Evaluating the person with chronic pain as a whole by identifying and under-
standing both their risk and protective factors. Unaddressed risk factors may
lead to treatment failure. Thus, using a broader conceptual basis with a human
systems approach and a shift in patient-centered clinical paradigms implicit
in the clinician-patient relationship will be the key to success.
2. Improving the safety of treatments to minimize the development of orofacial
disorders as an adverse event. This is particularly true of adverse events from
different types of surgery, dental procedures, chronic opioid use, and side
effects related to drug-drug interactions.
3. Implementing a transformative model of healthcare through a team approach.
A transformative care model includes risk assessment, robust self-management
training, and evidenced-based biomedical treatments to improve the out-
comes of pain management while reducing the patient’s dependency on the
healthcare system. Teams of healthcare professionals that may include a
patient-centered pain coach will play a growing role in training and support-
ing patients in self-management, particularly since they are also supported in
most health reform efforts.
4. Continuing medical and dental education (CE) courses that review the funda-
mentals of this new approach to care. Make use of the online CE course at
www.coursera.org/learn/chronic-pain and the transformative care toolkits to
implement online self-management training with evidence-based treatments
as part of the new routine of care [40, 41].
5. Supporting resources to help implement transformative care. Organizations
like the International MYOPAIN Society (www.myopain.org) through their
Campaign for Preventing Chronic Pain and Addiction (www.preventing-
chronicpain.org) [42] have goals to increase research, develop strategies,
expand education of both patients and health professionals on how to prevent

chronic pain using online training toolkits to implement a transformative care
model, increase advocacy and awareness, and provide media toolkits to
health plans, businesses, government agencies, and communities to improve
their efforts in preventing chronic pain.
By accomplishing these goals, we will address the Institute for Healthcare

Improvement’s triple aim of improving the experience of care, enhancing health,
and reducing the cost of healthcare for patients with pain conditions [43].
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Integrative Approaches to Orofacial
Pain: Role of Biofeedback and Hypnosis 27
Gabriel Tan, Alan Glaros, Richard Sherman,
and Chin Yi Wong
Pearls of Wisdom
• EMG biofeedback procedures in which patients are shown their levels of
masticatory muscle tension and taught to recognize and then control ten-
sion levels is a highly effective way to treat muscle tension-based orofacial
pain.
• Biofeedback-based interventions are at least as effective as traditional den-
tal and medical therapeutic approaches for muscle related pain and may
last indefinitely.
• Biofeedback for recognizing and then controlling sustained levels of jaw
muscle tension works best when patients learn the skills thoroughly and
then continue to practice them.
• Patients will probably benefit most by consulting with well-skilled and
appropriately credentialed biofeedback providers [21].
• Hypnosis and hypnotherapy could also contribute to management of the
orofacial pain by adding the elements of altering pain perception and expe-
rience, and improving motivation to respond to treatment.
• Acquisition and maintenance of a low level generalized relaxation state is
counter to the experience of TMD pain.
G. Tan, PhD, ABPP (*) • C.Y. Wong, BSocSci

Department of Psychology, National University of Singapore, Singapore, Singapore
e-mail: gtan46@gmail.com
A. Glaros, PhD
University of Missouri-Kansas City, Kansas City, MO, USA
R. Sherman, PhD
Psychophysiology Program, Saybrook University, Oakland, CA, USA

DOI 10.1007/978-3-319-51508-3_27
318 G. Tan et al.
27.1 Introduction
Temporomandibular (TMD)-related orofacial pain is caused by sustained masticatory

muscle tension. While sustained activation of the masticatory muscles accounts for a
very large proportion of the variance in pain, other factors, including genetic vulner-
abilities, stress, and autonomic dysregulation can also play a role in orofacial pain.
27.2 Rationale for Integrative Approaches to Orofacial Pain
Current scientific knowledge about TMD pain, especially myofascial pain in the
orofacial region, has changed dramatically in recent years. At least three mutually
complementary approaches to understanding the disorder have emerged. One
emphasizes that individuals with particular genetic vulnerabilities are particularly
responsive to stress and more likely to develop pain in the future [23]. A second
approach addresses autonomic dysregulation that characterizes individuals with
masticatory muscle pain and with chronic pain more generally [18]. A third approach
focuses specifically on the actions of the masticatory muscles and the impact of
sustained tooth contact/low-level activation of the masticatory muscles in TMD
pain [10].
Taken as a whole these three approaches suggest that an integrated approach that
helps patients manage stress, reduce autonomic dysfunction, and decrease mastica-
tory muscle tension will reduce pain. In the sections that follow, we will review the
available evidence that address these three main points, emphasizing so-called com-
plementary and alternative approaches to this problem. Importantly, all the treatment
strategies described in this chapter are consistent with the U.S. National Institutes of
Health’s strong recommendation that providers use conservative, reversible thera-
pies in those with TMD pain and avoid invasive, irreversible treatments.
We will focus primarily on myofascial pain in the orofacial region. There is little
evidence that biofeedback and hypnosis have particular benefit treating pain caused
by degenerative changes in the hard tissues of the temporomandibular joint (TMJ).
Similarly, there is little evidence that dysfunction of the soft tissues in the TMJ (e.g.,
displacement of the articular disc) can be successfully managed by the techniques
described in this chapter. Instead, we will focus on myofascial pain, as defined by
the Diagnostic Criteria for Temporomandibular Disorders (DC/TMD) [17], where
the available evidence base is quite encouraging.
27.3 Integrative Therapies to Orofacial Pain
27.3.1 Stress Management
Long-term studies convincingly show that individuals with particular variants in the
genes that code for catechol-O-methyl-transferase (COMT) are vulnerable to the
effects of stress (e.g., [23]). There are also multiple studies showing that
27 Integrative Approaches to Orofacial Pain: Role of Biofeedback and Hypnosis 319
cognitive-behavioral therapy (CBT), a well-established system for teaching indi-

viduals how to better manage stress and reduce pain, can effectively treat individu-
als with the myofascial pain of TMD. For example, a review of psychosocial
interventions for the Cochran Database of Systematic Reviews [4] found 17 trials
eligible for inclusion in the review. These trials showed a reduction in long-term
pain intensity and depression. A more fine-grained analysis showed that CBT, either
alone or in combination with biofeedback, improved long-term pain intensity, activ-
ity interference, and depression.
27.3.2 Control of Autonomic Dysfunction
An individual with TMD pain will, by definition, report discomfort in the muscles
of mastication or in the TMJ. However, pain in an individual diagnosed with TMD
is frequently accompanied by pain in the neck, shoulders, and upper and lower back.
TMD patients also frequently report a variety of headaches. These findings suggest
that a common mechanism may underlie the complaints of pain.
One promising strategy has examined autonomic functioning in individuals
with masticatory muscle pain (MMP). In one study, 22 individuals with mastica-
tory muscle pain and 23 non-pain control participants took part in three-part
study examining physiological activation and emotional reactivity during base-
line, stressor, and recovery periods. Physiological activity was assessed with fre-
quency domain heart rate variability (HRV) indices. The results showed that the
MMP patients had more physiological activation during the baseline period and
significantly more physiological activation during the recovery period compared
to the pain-free controls [18]. Similar findings using multiple measures, includ-
ing computerized pupilometry, confirm the presence of dysregulation in TMD
patients [5, 13].
These findings suggest that treatments targeting dysregulation may have a ben-
eficial impact. In one such study, individuals with chronic pain practiced a diaphrag-
matic breathing techniques designed to influence HRV. Those who practiced the
technique the most also were better able to tolerate pain generated by a cold-pressor
test [19]. Although these results are quite promising, considerably more research
needs to be carried out to evaluate the benefits of treatments that minimize auto-
nomic dysregulation on pain in TMD patients.
27.3.3 Decreasing Masticatory Muscle Tension via Biofeedback
Both experimental and observational studies indicate that masticatory muscle ten-
sion is very strongly associated with TMD pain [9], with muscle tension accounting
for nearly 70% of the variance in facial pain. Longitudinal multi-level modeling
examining the impact of stress, emotional distress, and muscle tension on facial
pain points to muscle tension as a causal factor in facial pain, also showing that
muscle tension accounts for about 70% of the variance in facial pain, an
320 G. Tan et al.
extraordinarily high value. These findings suggest that control of muscle tension
will have a clinically significant benefit in those who suffer from chronic facial pain
(e.g., [11]).
Multiple biofeedback modalities can be used to treat TMD-related myofascial ten-
sion-related pain. Not surprisingly, the most common modality is EMG biofeedback.
EMG biofeedback can be used in various ways to help those with myofascial pain.
When the teeth are separated by 4–6 mm, the activity of the masticatory muscles
(i.e., the masseters and temporalis) reaches a baseline minimum. Bringing the teeth
in contact increases the activity of these muscles between 2.0 and 3.5 times over the
relaxed baseline level. And, increasing the contact pressure between the teeth will
increase the activity of the masseters and temporalis muscles even more.
Interestingly, many TMD patients are not aware that their teeth are in contact or
that the masticatory muscles are activated. Similarly, TMD patients may not be
aware of the length of time that their teeth are in contact during the day (up to 75%
of waking hours). The reasons for this lack of knowledge may stem from problems
in proprioceptive awareness in those with masticatory muscle pain or from a defini-
tional problem involving the concept of “clenching.” Patients with TMD pain may
not be as accurate in their reports of internal states as those without pain, especially
when stressed. Alternatively, patients may believe that their personal tooth contacts
are “normal,” but they may not be aware of the amount of time when the teeth are
touching (a form of clenching, to be sure) [9]. These findings suggest that increasing
awareness of tooth contact and changing patient definitions so that any unnecessary
tooth contact becomes defined as clenching can be a reasonable starting strategy for
assisting those with TMD pain.
Biofeedback techniques can be used to illustrate the degree of change that occurs
in the masticatory muscles when the teeth are in contact or when individuals are
clenching. Electrodes can be placed on the surface of the skin above the main body
of the masseters and temporalis muscles, and the feedback display can be set to
show individuals how much EMG activity changes with even very slight tooth con-
tact. Seeing the impact of tooth contact, in real time, can provide very convincing
evidence to those suffering from myofascial pain of the need to control masticatory
muscle activity and reduce tooth contact.
Standard EMG biofeedback techniques with the aim of reducing masticatory
muscle activity can then be used to help individuals learn the necessary skills. The
activity in these muscles is highly dependent on jaw position and tooth contact. If
individuals are instructed to allow their teeth to separate, they can quickly learn to
reduce the activity of the masticatory muscles and then to learn the subtle signs of
increased masticatory muscle activity. Individuals can also be exposed to relevant
stressful stimuli and utilize feedback to maintain relaxation in the masticatory mus-
cles. There is considerable evidence showing that EMG biofeedback is an effective
treatment for those reporting TMD pain. Used alone, biofeedback improves pain,
pain-related disability, and mandibular functioning [8]. Multiple reviews and meta-
analyses conclude that EMG biofeedback is an effective treatment for TMD-related
pain (e.g., [4, 6]). Furthermore, studies comparing EMG biofeedback-based treat-
ment to traditional dental treatments (i.e., mouth guards or “splints”) show that
biofeedback is at least as effective as splints and other standard techniques (e.g.,

[7]). The studies using EMG biofeedback report treatment effectiveness lasting up
to 2 years (e.g., [7]), longer than the benefits generated by splints and CBT.
The process of EMG biofeedback training can be summarized as a three-step
process involving increasing awareness of muscle tension, calibration, and control.
As these examples make clear, these clinical strategies deliberately build in gener-
alization strategies to help patients learn and utilize newly-learned skills in their
everyday lives [20].
1. Awareness of masticatory muscle tension

(a) First in the office while looking at the biofeedback display
(b) Then in the office without the need of the display
(c) Then at home
(d) Then in the stress-producing environment
2. Calibration
(a) People with chronic masticatory muscle tension cannot tell how tense their
painful muscles are as accurately as they can tell how tense non-painful
muscles are.
(b) Biofeedback is used to teach people to accurately calibrate their muscle ten-
sion by having them tense to 25%, 75%, or 50% of max (at random), watch
the display, attend to the sensations produced, and then tense to the given
extent accurately without the display.
3. Control
(a) Everyone reacts physiologically to stress.
(b) Nobody can be trained not to react, but people can control the extent and
duration of the reaction.
(c) Patients can learn to avoid keeping muscles tenser than necessary for longer
than necessary
(i) First in the office
(ii) Then at home
(iii) Then in the stress-producing environment
As mentioned earlier, individuals with myofascial pain appear to have autonomic

dysfunction. In addition to relaxation strategies, individuals may also benefit from
biofeedback modalities such as HRV biofeedback or other psychophysiological
techniques to reduce the degree of dysfunction in autonomic functioning. Cognitive
restructuring can also be used to assist patients in minimizing physiological
responses to stress.
27.3.4 Hypnosis and Hypnotherapy
Hypnosis is used to alter pain perception, increase openness to suggestion, alter

emotional states (e.g., anxiety), and change behavioral activities/habits (e.g., mus-
cle tension and bracing; body posture) which may be contributing to the experience
322 G. Tan et al.
of pain. With respect to the three elements on targeting TMD pain previously dis-
cussed, hypnosis would be most applicable in regulating autonomic dysregulation,
reducing masticatory muscles tension, and correcting sustained tooth contact/low-
level activation of the masticatory muscles.
A meta-analysis of 18 studies utilizing hypnosis as analgesia across vari-
ous pain conditions found that 75% of patients experienced substantial pain
relief [14]. Reviews of controlled trials [12, 15] have also shown the ability of
hypnotic treatments to reduce pain perception in comparison to non-hypnotic
interventions.
However, hypnosis for the treatment of orofacial pain specifically has been less
common, with most studies focusing on headaches [12]. Recent studies have shown
promise in addressing this gap. For TMDs, Simon and Lewis [22] reported signifi-
cant decreases in pain and increases in daily functioning for recalcitrant patients,
with treatment gains maintained at follow-up and decreases in medicine usage.
Abrahamsen et al. [2] also found significant reduction in pain intensity for hypnosis,
compared to baseline and non-hypnotic relaxation.
Abrahamsen et al. [3] studied oral functions and psychological outcomes for
TMD patients, randomized to hypnotic intervention or simple relaxation. Pain
scores decreased significantly only in the hypnosis group with a significant increase
in usage of ‘reinterpreting pain sensations’ as a coping strategy. However, both
groups experienced significant decreases in painful muscle palpation sites, awaken-
ings, somatisation, obsessive-compulsive symptoms and anxiety. Thus, hypnosis
appears to be uniquely effective only in some areas of TMD.
Abrahamsen et al. [1] found similar reductions in pain scores with the treatment
of persistent idiopathic orofacial pain (PIOP). Patients more susceptible to hypnosis
also experienced a greater decrease in pain. Hypnosis aided in dealing with PIOP,
dependent on hypnotic suggestibility. Winocur et al. [25] assigned myofascial pain
patients to hypno-relaxation, occlusal appliance or education/advice. The first two
conditions were more effective in alleviating sensitivity to palpation, but a signifi-
cant decrease in pain was seen only in hypno-relaxation.
Although there is a paucity of randomized controlled trials showing the effi-
cacy of hypnosis in the treatment of orofacial pain, the above studies display the
potential of this method in alleviating or managing pain disorders. Stam et al.
[24] reported that suggestibility scores of facial pain patients predicted decreases
in pain experience following treatment. These findings suggest that the efficacy
of hypnosis in treatment of orofacial pain disorders is dependent in part on
patient characteristics and preference. This could be tested with other alternate
treatments, and patients could be pre-assessed to identify a suitable modality in
managing their pain conditions. Additionally, as concluded by Pistoia et al. [16],
treatment is most effective when a variety of therapies are used, including behav-
ioral and pharmacological interventions. Pain management is most effective
when an integrative, multidisciplinary approach is utilized, combining multiple
treatment modalities.
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Part X
A Comprehensive Approach
to Orofacial Disorders
History Taking and Physical Examination
for Orofacial Disorders 28
David Ojeda Díaz and Thomas P. Sollecito
28.1 Introduction
As clinicians our goal is to give our patients an answer to their concerns, a relief to
their suffering, and ultimately (when available) a cure to their illness. This will be
possible, only if we carefully follow a series of diagnostic steps, where every detail
is important. To develop consistency in the diagnosis of orofacial disorders, a con-
cise, thoughtful history and physical examination are essential.
The history and physical examination should be based on the specific complaint,
while being mindful of the etiology, epidemiology, and pathophysiology of various
possible diagnostic entities. The presenting signs and symptoms, temporal charac-
teristics, modifying factors, onset and course of the disease should be obtained,
using the knowledge, skills, and values of the clinician. The history and physical
examination is based on the type of orofacial complaint presented by the patient. In
this chapter we will discuss a systematic way to conduct a history and physical
examination to assess various orofacial disorders and successfully reach a
diagnosis.
D.O. Díaz, DDS (*)

Department of Oral Medicine, Penn School of Dental Medicine, University of Pennsylvania,
Philadelphia, PA, USA
e-mail: davidojedadiaz@gmail.com
T.P. Sollecito, DMD, FDS, RCSEd
Department of Oral Medicine, Penn School of Dental Medicine, Oral Medicine Division,
Penn Medicine, University of Pennsylvania, Philadelphia, PA, USA

DOI 10.1007/978-3-319-51508-3_28
328 D.O. Díaz and T.P. Sollecito
28.2 Oral Mucosal Diseases
Mucosal diseases affect an important segment of the population and can be debili-
tating. The evaluation, diagnosis and treatment of mucosal diseases involving the
oral cavity, represent an essential element of the oral medicine discipline. Mucosal
diseases of the oral cavity affect the mucosal lining of the mouth, including struc-
tures such as the gingiva, buccal mucosa, tongue, floor of the mouth, and hard and
soft palate. These conditions can arise from multiple etiologies and can present in
various patterns. The identification of specific patterns helps clinicians categorize
conditions and aids in arriving an accurate diagnosis.
One difficulty facing clinicians managing a patient with a mucosal disorder, lies
in the fact that most oral lesions appear similar clinically. Therefore, it is extremely
difficult to diagnose based on the examination only [1]. In order to reach a precise
diagnosis, one needs to develop a systematic method of inquiry, leading to a list of
diagnostic possibilities. A differential diagnosis list should be created based on the
history and physical examination and by drawing on fundamental knowledge and
the use of critical thinking to order the possibilities. The next diagnostic step might
include laboratory studies, imaging, biopsies, or other methods to narrow the list or
to arrive at a final diagnosis.
28.2.1 Medical History
A detailed medical history is at the foundation of an accurate diagnosis. The clini-

cian must conduct an interview, which, through a series of questions, will reveal the
medical status of the patient. A skilled clinician should use the data gathered to
assess and understand the patient’s concern, achieve a diagnosis, and propose a
management strategy [2].
The medical history should include identification of the patient along with demo-
graphic information, useful for epidemiologic purposes. After the demographic infor-
mation is recorded, the first step in a medical history is the chief complaint. The chief
complaint is (the patients stating in their own words) the reason they are seeing you.
The history of present illness (HPI) follows and is a description of the details regarding
the present condition and will provide a dimension of the problem. The HPI should
include attributes of symptoms describing the chief complaint. The past medical his-
tory will gather the general health information of the patient such as previous and cur-
rent medical conditions, diagnosis, and treatments; it also contains the past surgical
history, a medication history, and allergy history. The dental history includes previous
dental procedure, treatments, and experiences. A family history is necessary to deter-
mine possible genetic implications of diseases and should include pertinent informa-
tion about the patient’s blood relative’s health history. A social history includes previous
and current employment and use of alcohol, tobacco, and recreational drugs. Finally, a
review of systems is a comprehensive review of all of the systems of the body, monitor-
ing for signs and symptoms related to disease. It is extremely important to update the
medical status of the patient every office visit, including new medical diagnoses,
changes in medications or dosages, and new allergies.
28 History Taking and Physical Examination for Orofacial Disorders 329
28.2.2 History of the Present Illness (HPI)
It is the section of the medical history where the clinician needs to be inquisitive,
because the data will provide invaluable information regarding the current patient’s
condition. The HPI should be presented in a narrative fashion and chronological
order [3], taking into consideration underlying medical conditions, signs and symp-
toms, onset, severity, triggers, modifying factors, previous medical opinions or
diagnoses, past medications used for the condition, and imaging and laboratory
studies done previously.
Specially for patients with mucosal disease, four questions of the condition need
to be clearly established in order to be able to understand the nature of the problem;
these are:
1. Acute vs chronic:
Ask the patient if the symptoms developed recently or been present for over a
month.
2. Single vs multiple:
Refers to the number of lesions in the oral cavity.
3. Primary vs recurrent:
Differentiate between a first episode and a repeated episode.
4. Local vs systemic:
Inquire about oral mucosa involvement solely or manifestations in any other part
of the body.
In mucosal diseases the clinical examination is limited to inspection and palpation,

and the main goal is to differentiate normal from abnormal. The inspection process
should begin on the initial sight of the patient. A comprehensive and extended oral
cavity examination have should be performed in a systematic manner to minimize
oversights. All tissues of the oral cavity and visible oropharynx have to be exam-
ined. The findings should be recorded in detail (location, size, shape, color, consis-
tency, base of the lesion, and surface appearance) using proper medical jargon
(papule, tumor, nodule, vesicle, pustule, fissure, erosions, ulcer, plaque, macule)
(Table 28.1) (Figs. 28.1 and 28.2). Palpation is also fundamental to the exam and
will provide more clinical information such as consistency (firm, hard, soft, indu-
rated, fluctuant), temperature, or pulsation. The manipulation of the lesion could
also provide valuable information regarding the nature of the mucosal disease (peel-
ing, draining, wipeable, friable). Palpation of the cervical lymph nodes is manda-
tory and should include pre- and postauricular, anterior cervical, deep cervical,
posterior cervical, supraclavicular, submandibular, and submental lymph nodes.
Normally, lymph nodes in general should be not palpable. If palpable, a description
of the nodes’ consistency, mobility, sign, and symptoms is required.
Technology has provided a useful tool in helping assessment in mucosal diseases
in the oral cavity. Clinical photography is an easy and economical way to document
Table 28.1 Oral mucosal lesions nomenclature [3]

Lesion Definition
Papule Superficial, solid, elevated lesion less than 1 cm in diameter
Pustule Vesicle filled with purulent fluid
Tumor Solid elevated lesion greater than 2 cm in diameter
Nodule Solid, elevated lesion, larger than a papule and smaller than a tumor
Vesicle Superficial, elevated, well-circumscribed lesion less than 1 cm in diameter
Bullae Superficial, elevated, well-circumscribed lesion greater than 1 cm in diameter
Erosion Depressed lesion resulting from loss of epithelium
Ulcer Depressed lesion resulting from the loss of epithelium and connective tissue
Fissure Deep linear lesion on the connective tissue
Macule Circumscribed, non-palpable discoloration less than 1 cm in diameter
Plaque Solid, flat elevated lesion greater than 1 cm in diameter
Fig. 28.1 Tumor on the

tongue
and monitor oral lesions, due to the availability. Clinical photography allows a closer
examination of the surface of the lesion and perhaps allow for the ability to monitor
changes in the lesion over time. It could also help educate a patient regarding their
condition. Clinical photography must be practiced following the principles of auton-
omy of the patient, supported by a consent and according to local privacy rules.
28.2.4 Diagnostic Tests
On those occasions where the diagnosis cannot be reached base on the medical his-
tory and physical examination, further diagnostic tests are needed. There are innu-
merable diagnostic techniques available and should be only requested to answer a
Fig. 28.2 Nodule on the

tongue
specific clinical question about the possible diagnosis and not as a routine [4]. The
clinician has to be mindful of the limitations, sensitivity, and specificity of each test
to interpret the result and accurately reach a diagnosis. Microbiological cultures,
Gram smears, and polymerase chain reaction (PCR) are only few examples of
methods commonly used in oral medicine (see other chapters for indications).
28.2.5 Adjunctive Techniques for Oral Mucosa Examination
Due to the similar appearance of many mucosal diseases, adjunctive diagnostic

techniques have been developed to facilitate the detection of oral premalignant and
malignant lesions. These techniques are based on the ability of the tissues to behave
under certain stimuli, when metabolic or structural changes are present. Adjunctive
techniques have been divided into visual tissue staining, visualization adjuncts,
advanced cytopathology [5], and molecular technologies. With different levels of
sensitivity and specificity, further study is needed to refine their use in a generalized
patient population administered by the general dentist. None of these techniques are
substitutes for the surgical biopsy with histological examination, which is the gold
standard method to diagnose mucosal diseases.
28.2.6 Serologic Studies
On occasion laboratory tests are required and could be ordered based on the medical
history, physical examination and intra oral findings. Laboratory studies are indi-
cated to determine the health status of the patient, to rule out systemic disease and
monitor side effects of medications.
Routine blood test such as complete blood count (CBC) with differential and
comprehensive metabolic panel (CMP) are tests used to help diagnose a suspected
condition, with screening purposes, or to monitor infections, anemia, diabetes, liver
and kidney functions which may relate to the oral condition. Other more specific
laboratory tests, such as SSA/SSB, antinuclear antibodies (ANA), and rheumatoid
factor, could help to diagnose autoimmune disorders. Levels of iron, ferritin, vita-
min B12, and folate may provide useful information about possible deficiencies and
their impact in oral health and disease.
28.2.7 Surgical Biopsy
Biopsy is a surgical procedure where a sample of tissue is taken for histopathologic

evaluation. Two surgical biopsy techniques are described: incisional and excisional.
Incisional biopsy is a procedure where a small sample of tissue is taken from the
lesion and is indicated in large lesions or when potential malignancy is suspected.
Excisional biopsy is a surgical procedure where the entire lesion is removed and is
often considered the treatment. It is indicated in benign, smaller lesions. The proce-
dure is usually done in outpatient settings, with local anesthesia and is associated
with minimal complications. Routinely the tissue samples are transported and fixed
in 10% formalin and sent to the pathology laboratory for hematoxylin and eosin
(H&E) staining. In most of the cases after a histological examination under light
microscopy, a diagnosis is offered (Fig. 28.3). Other staining techniques are
Fig. 28.3 H&E staining of lichenoid mucositis (Courtesy Dr. F. Alawi)

available and are used when the selective staining of cells or cellular components is
required. In certain occasions staining for particular infectious agents may also be
warranted.
When a diagnosis cannot be achieved through H&E or other staining techniques
and autoimmune disease with oral manifestations is suspected, immunofluores-
cence testing is indicated. Autoimmune diseases are characterized by production of
specific autoantibodies; identification of the antibodies and the tissues against they
are targeted is important to reach a diagnosis [6].
There are two types of immunofluorescence techniques described: Direct immu-
nofluorescence (DIF) consists in the application of fluorescein-conjugated antihu-
man Ig antibodies to the patient’s tissue specimen containing disease-specific
antibodies. If it is positive, a green fluorescence is seen in the patient’s tissue speci-
men when viewed with UV light (Fig. 28.4). Indirect immunofluorescence (IIF)
uses the patient’s serum with disease-specific antibodies which bind to homologous
structures in an animal tissue specimen, and then fluorescein-conjugated antihuman
Ig antibodies to animal tissue specimen containing the patient’s disease-specific
antibodies are applied. If it is positive, the animal’s tissue specimen will glow when
viewed with UV light [7].
When DIF is planned, Michel’s solution (as a conservation and transportation
medium) needs to be used in order to preserve immune antigenicity of the tissue
sample and ensure an accurate diagnosis. More recently normal saline solution
has shown to be also effective, but the tissue sample has to be processed within
24 h [8].
Fig. 28.4 Direct immunofluorescence showing fibrogen (Courtesy Dr. F. Alawi)

28.3 Salivary Gland Disorders
The salivary glands are exocrine glands that play an important role in digestion.
They are divided into two groups: the major salivary glands and the minor salivary
glands. The major salivary glands (composed of the parotid, submandibular, and
sublingual) are distributed in pairs, symmetrically on both sides of the head and
neck area. While the minor salivary glands are located throughout the mucosal lin-
ing of the oral cavity, both groups are responsible of the production and secretion of
saliva, which plays an important role in the homeostasis of the mouth [9].
To effectively assess the salivary glands, it is important to understand their anat-
omy and the relationship with other important anatomic structures including the
facial nerve and the facial artery. One must also understand the possible etiologic
factors causing the signs and symptoms of disease such as autoimmune disorders
(Sjogren’s syndrome), infectious diseases (bacterial or viral parotitis, HIV, etc.),
and neoplastic processes. Finally, one must understand the physiology of the glands
in mastication and sleeping.
Salivary gland disorders can be suspected subjectively in the setting of symp-
toms, most commonly oral dryness, and less frequently associated with pain. But
salivary gland disorders can also manifest objectively with signs of a swelling, mass
in a gland, or objective hypofunction. Patients with salivary gland dysfunctions can
develop local and systemic complications, and therefore a careful history and exam-
ination will ensure a proper diagnosis.
28.3.1 Medical History
The medical history plays a key role in establishing a differential diagnosis of sali-
vary gland disease, due to the relationship of the salivary gland with systemic disor-
ders. An accurate medical history should establish the complaint and the magnitude
of the complaint. When the patient’s medical history is consistent with conditions or
medications that are known to affect salivary function, the diagnosis is often easily
determined. If during the history of present illness or the review of systems, a patient
reveals symptoms that are associated with salivary gland dysfunctions, more refined
diagnostic methods may be needed to rule out underlying pathology.
Previous and current medications deserve special attention during the medical
history, since there are known relationships between certain medications and salivary
gland dysfunction. The exact pathophysiologic mechanism involved in medication-
induced salivary gland dysfunction is not easily explained, due to the multiple ways
this phenomenon could occur. Drugs can interact simultaneously with different nerve
inputs at different levels, affecting salivary gland stimulation. Furthermore, poly-
pharmacy could even increase the xerogenic potential of other medications [10]. The
most common medications associated with xerostomia are antidepressants, antipsy-
chotics, anticholinergics, antihypertensives, antihistamines, and sedatives [11].
Xerostomia is the most common subjective complaint of salivary gland dysfunc-
tion [12]. Although diminished salivary flow is a logical reason to experience dry
mouth, studies have shown that xerostomia is not always accompanied by salivary
Table 28.2 Fox questionnaire

Response
Question Yes/No
1. Does the amount of saliva in your mouth seem to be too little and too much,
or you do not notice it?
2. Do you have any difficulty swallowing?
3. Does your mouth feel dry when eating a meal?
4. Do you sip liquids to aid in swallowing dry food?
gland hypofunction. Many methods to identify and categorize patients with dry
mouth complaints have been proposed in order to establish if the xerostomia is
related to salivary hypofunction. Fox et al. were pioneers developing a system
(questionnaire) which predicts salivary gland hypofunction, based on the patient
perspective [13] (Table 28.2).
Salivary glands are located superficially in the head and neck region which facilitate
inspection and palpation during a physical exam. Initial evaluation requires a care-
ful extraoral inspection based on side to side comparison, looking for asymmetry
and discoloration. Parotid involvement is perhaps easily recognizable due to the
location of the gland and association with preauricular swelling. Submandibular
glands may exhibit enlargement anterior and medial to the angle of the mandible
while sublingual glands are not possible to inspect extraorally. Usually, bilateral
involvement of the salivary glands implies systemic disorders whereas unilateral
involvement favor local pathology. Due to the close proximity between the parotid
glands and cranial nerve VII (facial nerve), motor function could be tested to rule
out neurologic involvement. Intraoral inspection is also important, integrity of the
salivary glands and ducts as well as the preservation of their excretory functions
should be assessed by palpation.
During extraoral palpation, masses should be assessed, particularly in the context
of febrile illness. To maximize the submandibular gland exposure, it is recom-
mended to incline the patient’s head forward and slightly flex the neck. Typically,
salivary glands palpation is painless or with mild discomfort, and the consistency
should be rubbery but not hard. Bidigital palpation (extraoral and intraoral) is rec-
ommended looking for possible masses while assessing function. With both hands
gloved, one inside the mouth and the other on the face, compression for few seconds
should be applied to the major salivary glands, in a milky fashion looking for clear
copious saliva.
Minor salivary gland assessment is performed by overall inspection of the oral
cavity with special attention on the labial mucosa and the hard and soft palate.
Stretching of the upper and lower lip should expose minor salivary glands and reveal
a wet nodular surface. In patients with minor salivary gland atrophy as a conse-
quence of salivary gland dysfunction, the result is the tendency for the lower lip to
sticking to the teeth.
Fig. 28.5 Cervical decay
Salivary gland dysfunction has significant repercussions in the mouth environ-

ment. The oral mucosa, lips, and teeth are usually affected. The lips may be dry,
cracked, and peeling. The buccal mucosa may look corrugated and shiny to the light
while the tongue tends to appears smooth (devoid of papilla) and reddened. Patients
are prone to develop cervical and incisal dental decay (Fig. 28.5) due to the accumu-
lation of food debris in areas where usually the saliva would otherwise act as a
cleaner. Local complications in patients with hyposalivation are common, including
candidiasis involving the tongue and palate. Angular cheilitis of the mouth is quite
common as well (Fig. 28.6).
28.3.3 Saliva Collection
In order to objectively determine salivary gland function, salivary flow rates needs
to be measured, this is called Sialometry. Different techniques for collection are
implemented depending on the aim. For general assessment “whole saliva”
(understood as a collection of a mixed sample of oral fluids) is recommended. In
contrast, individual major salivary gland function is mostly used for research
purposes.
The “spitting method” is the most widely used. It is a simple method to deter-
mine unstimulated “whole salivary” flow. The patient should be seated in a vertical
Fig. 28.6 Dry mouth with

angular cheilitis
Table 28.3 Saliva flow rates [14]

Salivary flow (mL/min)
Normal stimulated salivary flow 1.5–2
Normal unstimulated salivary flow 0.3–0.4
Hyposalivation stimulated salivary flow ≤0.5–0.7
Hyposalivation unstimulated salivary flow ≤0.1
position, accumulating the saliva in the mouth for 5–15 min without swallowing.
The patient is asked to spit in a pre-weighed tube every 60 s.
Stimulated “whole saliva” can be obtained using a standardized and reproducible
method of chewing an unflavored gum or a paraffin wax at a controlled rate (60
times per minute) for 1 min. Stimulating salivary secretion with a 2% citric acid
solution by placing on the tongue in intervals of 30 s, while collecting the saliva on
a graduated tube for 5 min can also be used. To ensure accurate measures, it is
important to abstain the patient from eating, drinking, and smoking or have any oral
stimulation for 90 min prior to the collection.
When an individual salivary gland function needs to be measured, more special-
ized equipment and time is required. For parotid flow measurements, an established
suction device called a Carlson-Crittenden collector is used. The collector has to be
attached to the Stensen’s duct, while an applied suction device extracts saliva through
a cannula from the salivary gland. Submandibular and sublingual salivary flow mea-
surements are more difficult due to the location of the excretory ducts. Although many
systems have been developed, there is no consensus regarding accuracy, reproduc-
ibility, and convenience/easement. One advantage of isolated saliva from a specific
salivary gland is that it can be analyzed not only quantitatively but also qualitatively.
General considerations for sialometry recommend to use a standardized and repro-
ducible method (time, position, environment). This will allow accurate, reproducible,
and comparative results and allow comparison of various therapies (Table 28.3).
28.3.4 Salivary Gland Imaging
When deciding to proceed with salivary gland imaging, the clinical scenario is one
of the most important considerations in choosing the correct technique. Many imag-
ing techniques are available and are useful to determine salivary gland function and
anatomic alterations.
28.3.5 Plain Film Radiography
When a salivary stone (sialolith) is considered in the differential diagnosis, a stan-

dard dental radiograph may be helpful to define location, size, and number of sialo-
liths. A mandibular occlusal radiograph will be able to capture the anterior floor of
the mouth and rule out a sublingual or submandibular sialolith. If a stone is sus-
pected in the parotid duct, an occlusal film placed in the buccal mucosa on the
Stensen’s duct opening can be considered. In cases when there is suspicion of a
deeper obstruction, a panorex, anterior posterior (AP) or lateral oblique radiograph,
may be beneficial. Plain film however is only useful in superficial cases, small or
poor calcified stones may not be visible.
28.3.6 Sialography
This technique allows the visualization of the salivary gland duct system on a radio-
graph, after the administration of a contrast medium throughout the duct. When
ductal obstruction (sialolith, tumor, or stricture) is presumed, sialography will allow
assessment of the ductal system of the salivary gland. A continuous track is expected
to be observed; blockage or dilatation of the contrast are indicative of pathology.
Radiographic studies such as panoramic, AP, and lateral oblique are used with this
technique. Sialography can be performed both for the parotid and submandibular
salivary glands. It is contraindicated in cases of allergy to the contrast dye.
28.3.7 Ultrasound (US)
Due to the superficial location of the salivary glands, ultrasounds may be beneficial.
High-frequency sound waves transmitted into the body will result in echo that will
be captured to create an image in two perpendicular planes [15]. This image allows
a very detailed but superficial study of the salivary glands. Ultrasound study has
shown to be very effective differentiating intra-glandular from extra-glandular
lesions as well as discriminating solid versus cystic lesions. Sialoliths are also visi-
ble and is helpful to determine glandular abscesses. When a malignant neoplasm or
vascular lesions are suspected, Doppler ultrasounds can estimate the blood flow
through blood vessels utilizing the same principle of high-frequency sound waves.
Ultrasounds are a noninvasive and cost-effective procedure. The most significant
limitation of ultrasound is the poor ability to evaluate the deep parotid lobe.
28.3.8 Radionuclide Imaging (RI)
RI or scintigraphy is a diagnostic test based on the ability of the radioisotope (tech-

netium) to bind to salivary gland proteins and release to the oral cavity following the
normal process of stimulation and excretion of saliva into the oral cavity. After an
intravenous administration of the radioisotope, an external detector captures the
radiation emitted to create a two-dimensional image. Only the parotid and the sub-
mandibular glands can be distinctly visualized [14]. It is considered a dynamic test
because it allows for the evaluation of the functional performance of the salivary
gland. It is also still considered a noninvasive procedure, since the wash out of the
radioisotopes is reached quickly upon salivary gland stimulation.
28.3.9 Computerized Tomography (CT)
CT scan is the result of multiple X-rays taken from different angles and processed
in a computer to create cross-sectional dimensional images of the organ to study.
The advantage of this technique is in its ability to evaluate both superficial and deep,
hard, and soft tissues in a great level of detail. CT is a versatile study; the application
of contrast medium will enhance structures for a detailed evaluation of tumors,
abscesses, blood vessels, and lymph nodes. This study is indicated to evaluate the
deep salivary glands, when there is a concern for neoplastic process or a concern
regarding the relationship to vital anatomic structures or when MRI is contraindi-
cated. Some disadvantages include the radiation exposure and the distortion of the
image due to dental materials, as well as allergies to contrast dye (iodine, barium).
28.3.10 Magnetic Resonance Imaging (MRI)
MRI uses a strong magnetic field and pulses of radio waves to generate detailed
images of organs in different sections/planes. Changes of the pulse sequence (T1
and T2) enhance the structure depending on the nature of the tissue. MRI is highly
recommended when neoplastic processes are suspected because of the exceptional
capacity to highlight soft tissues with better contrast resolution than any other imag-
ing. However, the ability to identify calcified lesion is not as robust as CT scan. The
MRI has become the preferred imaging method for salivary gland masses assess-
ment [16] and preoperative evaluation. MRI is contraindicated in patients with cer-
tain implants, claustrophobia, or difficulty keeping in an immobile position.
28.3.11 Positron Emission Tomography (PET)
PET is a functional imaging technique, useful to evaluate the metabolic process of

the glands. The system captures gamma rays from a radionuclide after being intro-
duced into the body. It is an accepted method to evaluate for malignancy. The
combination of PET and CT has shown to be more accurate in the evaluation of

metastasis. Treatment response and long-term surveillance are also common rea-
sons to order a PET scan [17].
28.3.12 Salivary Glands Biopsy
Biopsy is the gold standard method to establish a definitive diagnosis on salivary

gland tissue. Minor salivary gland biopsy is included as a major criterion to diag-
nose Sjogren’s syndrome. A routine H&E stain should reveal lymphocytic infiltra-
tion into the salivary gland acini [18]. Minor salivary glands can also be used to
diagnose amyloidosis, sarcoidosis, and monitoring graft-versus-host diseases [14].
The biopsy is an outpatient surgical procedure. After infiltration of local anesthesia,
an incision is made in the inner lower lip mucosa. Blunt dissection should be done
to expose the minor salivary glands with removal of five to ten glands. Regarding
Sjogren’s syndrome diagnosis, major salivary gland biopsies have not shown diag-
nostic advantage compared with minor salivary glands.
Biopsy of major salivary glands requires significantly more experience. Parotid
and submandibular gland biopsies are approach extraorally in contrast with sublin-
gual gland biopsy that is usually done intraorally.
Biopsies of major salivary glands are challenging due to their location and the
surgical risk which could compromise vital anatomic structures. When open biop-
sies cannot be done, fine needle aspiration (FNA) represents an alternative to an
open surgical biopsy. The technique is based on the ability to aspirate cellular sam-
ples from the gland using a needle, introduced manually into the salivary gland or
occasionally with the aid of ultrasound imaging. The sample collected is sent for
cytological evaluation.
FNA is widely accepted as a diagnostic tool for head and neck swellings, with
high rates of accuracy 73–98% [19]. If the sample is limited or the cytology is report
as inconclusive, an open biopsy may be indicated.
FNA has shown to be a reliable method used to differentiate between an inflam-
matory and a neoplastic process [20]. Fine needle aspiration is a convenient tech-
nique that does not require general anesthesia or preoperative testing; it is well
tolerated by most patients, while being cost-effective and associated with minimal
complications.
28.3.13 Serological Studies
Since salivary gland dysfunction has been associated with autoimmune and sys-
temic conditions, certain laboratory (blood) studies assist in reaching a diagnosis.
CMP will allow evaluation of blood glucose levels and help determining if salivary
glands enlargement is associated, for example with diabetes mellitus. Other nonspe-
cific blood tests for autoimmune markers, such as antinuclear antibodies (ANA),
rheumatoid factor, erythrocyte sedimentation rate, and antibodies directed against
SSA/SSB, are particularly useful to aid in the diagnosis of Sjogren’s syndrome.

High amylase levels detected in the blood serum could be associated with inflam-
mation in diseases such a viral or bacterial parotitis [21].
28.4 Orofacial Pain Disorders
Orofacial pain is understood as any painful condition involving the head, face,
and neck area. The diagnosis and appropriate treatment are complex, because
pain can arise from many different structures coexisting in a relatively small
anatomic area. The numerous structures and their intricate innervation and func-
tional interaction result in a wide range of diagnostic possibilities, often making
interdisciplinary collaboration necessary to achieve a correct diagnosis and treat-
ment [22].
Typically, patients with orofacial pain disorders consult multiple physicians
before getting a correct diagnosis and definitive treatment. Clinicians treating
patients with orofacial pain can avoid diagnostic errors by developing a careful and
systematic method to obtain an accurate and comprehensive history and a thorough
head and neck examination.
The differential diagnostic process should include broad various etiologies to
pain, including neurologic, vascular, infectious, musculoskeletal entities and the
combinations of them. The current definition of pain by the International Association
for the Study Pain (IASP) includes the “emotional experience associated,” which
means that the painful experience is influenced by psychological factors. Okeson
outlined a classification system where Axis I comprise the physical factors and the
Axis II the psychological factors [23]. Both should be assessed to understand the
etiology, the progression, and the prognosis of the condition.
In order to reach a diagnosis, it is important to understand the nature of the prob-
lem. Pain is subjective and dynamic and comprises sensations, emotions, and reac-
tions [24], and all of these features require careful evaluation.
28.4.1 Chief Complaint and History of the Present Illness
Orofacial pain patients often present to the office with multiple complaints accom-
panied by a level of anxiety and frustration. It is favorable to gather all possible
information and organize the data in a timeline to have an idea of the progression
and severity of the pain. The clinician has to be aware that pain is subjective and is
modulated by emotions and can be expressed or interpreted in different ways. For
some patients verbal communication of complex symptoms is challenging,
Providing examples (burning, stabbing, pressure, etc.) to the patient is often helpful
to understand and categorize the complaint.
The clinician should aim to establish the onset of the symptoms, location, quality
and quantity of the pain, duration and frequency, relieving and aggravating factors,
associated symptoms, and past diagnostic tests.
28.4.2 Location
Starting by determine the location of the pain will help to figure the extension of the
pain complaint. It is useful to ask the patients to use their fingers to point the area of
pain. Also drawing on a head and neck diagrams can be a convenient method for a
better understanding and communication between the patient and the examiner.
Because of the complex interactions between the multiple structures in the head
and neck area, do not assume the location of the pain is the source of the pain.
28.4.3 Onset
Determine when the symptoms started and the circumstances that initiated the pain,
are helpful as they might provide clues of the possible cause of pain. Local trauma
such as car accidents, sport injuries, and/or dental treatment are often clear initia-
tors. Cases with spontaneous onsets deserve a more detailed investigation. It is also
essential to listen the patient’s understanding of the time when the pain occurs, since
it will also offer helpful signs for the diagnosis.
28.4.4 Quality
The characteristics of the pain can offer clues about the etiology. Classically differ-
ent structures (nerves, muscles, teeth, etc.) express very particular types of pain
quality. Even though the description is based on subjective symptoms, if the precise
terms are used to describe the pain, different broad categories of disease entities
emerge (musculoskeletal, vascular, neurologic, etc.) (Table 28.4).
28.4.5 Quantity or Intensity
The intensity of the pain is important to set as a baseline and to monitor the success
or failure of the treatment. The intensity can be recorded verbally (mild, moderate,
or severe) or numerically from 0 to 5 or 0–10. The visual analog scale is the most
common and validated method used to categorize pain. On a 10 cm vertical line,
labeled on one end with “no pain” and on the other end “worst possible pain,” the
patient is asked to make a mark wherever his/her perception is the level of the pain.
Determining the severity of pain may also help to choose the treatment strategy.
Table 28.4 Quality of pain [24]

Pain Feature
Musculoskeletal Dull, aching, pressure, depressing, tightness
Vascular Throbbing, stabbing, pounding, rhythmic
Neurologic Bright, burning, itchy, electrical, cutting,
lancinating, sharp
28.4.6 Timing
Timing includes duration and frequency of the pain episodes, which offers valuable
information about the pattern of the pain. These features should be recorded in sec-
onds, minutes, hours, days, or months. The episodes may be described as paroxys-
mal, episodic, steady, intermittent, or continuous, according to the case.
28.4.7 Modifying Factors
Modifying factors refers to those factors that seem to modulate the pain sensation,
either aggravating or alleviating. As the head and neck area is involved in many vital
functions (speaking, chewing, swallowing, etc.), some of those processes could
aggravate (even trigger) or alleviate the pain. Other ordinary functions, like lying
down, yawning, brushing teeth, shaving, and washing the face, could also be a trig-
ger. It is important to inquire about parafunctional habits, either voluntary or invol-
untary (clenching, grinding, nail and lip biting). High levels of stress and poor sleep
quality are often seen and identified as modifying factors. The patient should be
advised to avoid known triggers and aggravating factors, while trying to alleviate
with different strategies (cryotherapy, moist heat, massages) the pain.
28.4.8 Associated Symptoms
Due to the complex neurologic interaction in the head and neck area, multiple asso-
ciated symptoms can be present. Autonomic phenomena, such as tearing, redness of
eye, nasal congestion, and rhinorrhea, can be associated with myofascial pain and
migraines [25]. These findings provide information of sympathetically mediated
etiology of the pain. The examiner must to be careful to not confuse the main com-
plaint with the concomitant symptoms.
28.4.9 Past Diagnostic Tests and Medications
By the time a patient consults a specialist, the patient probably has consulted other
physicians and has been treated with several therapies and medications. Recording
all previous treatments including over-the-counter products or by prescriptions,
with their respective outcomes, will optimize patient care.
28.4.10 Cranial Nerve Examination
Cranial nerves provide sensory and motor innervation to head and neck structures. A
systematic examination is essential and will facilitate a full assessment of the area.
With simple testing a gross cranial nerve examination will bring information regarding
the functioning of the 12 cranial nerve pairs, to rule out a central nerve component to
Table 28.5 Cranial nerve function [26]

Cranial nerve Test
I Olfactory Sense of smell
II Optic Visual acuity and visual field
III Oculomotor Eyeball movements, pupillary reflex, accommodation
IV Trochlear Down and out movement of the eyes
V Trigeminal Sensation on the three branches and masticatory muscles function
VI Abducens Lateral movements of the eye
VII Facial Movement of facial movements, special sensory taste (anterior 2/3 of
the tongue)
VIII Acoustic Hearing, equilibrium
IX Glossopharyngeal Elevation of the palate, movement of the pharynx and larynx. Sensation
of the palate and the posterior 1/3 of the tongue
X Vagus Muscles of soft palate, base of the tongue, pharynx, and larynx
XI Accessory Movement of the sternocleidomastoid and trapezius
XII Hypoglossal Movement of the tongue
the patient’s complaint (Table 28.5). Any deficiency or alteration should be recorded
and addressed by referring the patient to the respective specialist (often neurologist).
If the patient is complaining about specific symptoms such as paresthesia and
dysesthesia or if during the extra- and intraoral examination they manifest allodynia
or hyperalgesia, sensory testing to objectively assess the symptoms should be per-
formed. Light touch, pin prick, two-point discrimination, and thermal discrimina-
tion will help to “map out” the area of involvement.
28.4.11 Head and Neck Examination
The head and neck examination uses the basic principles of inspection, palpation, per-
cussion, and auscultation. It is recommended to evaluate the TMJ complex, the masti-
catory and cervical muscles, the lymph nodes, and the thyroid and salivary glands.
28.4.12 Temporomandibular Joint (TMJ) Evaluation
A comprehensive understanding of the TMJ anatomy and biomechanics is vital to

interpret the clinical findings of the TMJ evaluation. TMJ complaints are not limited
to pain, but also TMJ sounds and alterations in the range of motion. To fully assess
the TMJ, a static and dynamic evaluation has to be performed. With the fingers
placed over the TMJ area, light pressure is applied to determine if there is local pain
over the preauricular area to establish a diagnosis of capsulitis. The patient is
instructed to open and close the jaw slowly a few times for a dynamic evaluation.
The fifth digit is also placed into the ear canal while jaw movements are repeated.
Pain while performing this test may be a sign of retrodiscitis.
Joint sounds from the TMJ are often signs of biomechanical and/or structural
changes, which can also be assessed in a dynamic manner. With the help of a stetho-
scope placed over the TMJ area, the patient is asked to open and close few times.
Distinct clicks are indicative of articular disc displacement. Also crepitus can be
present in the TMJ, indicative of osteoarthritic changes of the TMJ. Joint sounds

may or may not be accompanied with pain.
Movements of the TMJ are evaluated through the range of motion, in search of
restrictions, interferences, or deviations. Alterations of the mandibular movement,
either a deviation or deflexion of motion, help in the diagnosis of joint disease.
Maximum opening with and without pain, passive opening, protrusion, and lat-
eral excursions will give information regarding the TMJ complex functioning. For
maximum opening measurements, the patient is asked to open as wide as possible
without pain (Fig. 28.7). If the patient is reporting pain while opening, he/she should
stop and that distance measured. When the maximum opening with or without pain
is obviously restricted, attempts to open wider with gentle distraction by the exam-
iner should be performed. This passive opening maneuver results in a sensation of
the stop being described as hard or soft.
Protrusion will provide information about condylar translation, and is assessed
when the patient is asked to move the mandible forward. For lateral excursive move-
ments, the patient is asked to slightly open the mouth and move as much as they can
from side to side (Fig. 28.8). Value in millimeters should be measured and recorded.
Fig. 28.7 Maximum
opening measurement
Fig. 28.8 Lateral
mandibular excursions
This maneuver will provide information of muscular functionality and TMJ internal
disarrangements. Restriction in movement will often indicate a medial or lateral
displacement of the articular disc.
28.4.13 Muscle Palpation
Palpation is the best method to directly assess the masticatory muscles, seeking for
tenderness or pain. Ultimately trigger points could be also identified. Normally,
palpation of the muscles should not provoke tenderness. Muscular palpation often
replicates the pain complaint when the muscle is involved. Once the source of pain
is identified, the pain severity is recorded. It may be prudent to ask the patient about
the use of analgesic prior the consultation, in order to consider its effect on the
symptoms during the examination [27].
Through palpation, a muscular pain diagnosis can be easily established. Trigger
points, which are hyperirritable foci located within a taut band or fascicle, are tender
upon palpation and will reproduce a predictable pattern of referred pain [28].
Despite the lack of consensus for the diagnosis of trigger points, as a general rule,
firm and steady pressure for few seconds has to be applied into the muscle in order
to be able to replicate the referred pain pattern.
The temporalis and masseter muscles should be assessed extraorally, in addi-
tion, the sternocleidomastoid, trapezius and digastric muscles should also be pal-
pated (Figs. 28.9, 28.10, 28.11, and 28.12). Intraorally the masseter origin,
temporalis insertion, and medial pterygoid should be palpated (Fig. 28.13). For
those masticatory muscles that are impossible to predictably palpate either intra-
orally or extraorally, such as lateral pterygoids, functional manipulation tech-
niques could be used to assess their role in the symptoms. Protrusive movement,
asking the patient to move the mandible forward, will test the lateral pterygoids
muscles function as well.
Fig. 28.9 Masseter muscle

palpation
Fig. 28.10 Temporalis
muscle palpation
Fig. 28.11 Sternocleido-
mastoid muscle palpation
28.4.14 Oral Mucosa and Dental Examination
Even when the patient’s symptoms do not seem to be odontogenic, an intraoral

evaluation should be done. Intraoral findings reveal valuable information especially
in regard to patient’s parafunctional habits. Crenations on the lateral borders of the
tongue and linea alba on the buccal mucosa are common findings in patients with
bruxism. Generalized wear facets on the dentition are also commonly found in
patients with parafunctional habits.
When the patient’s pain complaint mimics dental origin, a dental evaluation
should be considered, including radiographs or other imaging techniques, vitality
tests, and percussion and periodontal evaluation. Pulpitis, dental fractures, and peri-
apical processes should be also ruled out.
Occlusion should be grossly examined looking for changes. Currently there is no
evidence to support the relationship between malocclusion and orofacial pain disor-
ders. Changes in the occlusion can be considered the consequences of temporoman-
dibular disorders rather than the cause [24]. A baseline evaluation allows monitoring
the progression of any malocclusion.
Fig. 28.12 Trapezius
muscle palpation
Fig. 28.13 Intraoral medial

pterygoid muscle palpation
28.4.15 Diagnostic Anesthetic Injections
When the source of the pain is difficult to localize, anesthetic injections could be help-
ful. With a diagnostic block, the clinician might be able to identify the source of the
pain and also differentiate a centrally mediated process from a peripheral pain pro-
cess. There are three types of injections: muscular, nerve, and joint.
Muscular injections with local anesthesia are useful not only to help to determine
the source of the pain but also have a therapeutic value, and it may help to educate
a patient, regarding the concept of pain referral. Trigger points injections are tar-
geted to an active trigger point. The therapeutic efficacy of trigger point injections
is attributed to the mechanical disruption of the trigger point by the needling tech-
nique, rather than the anesthesia itself [24].
Nerve blocks are particularly useful to differentiate central sensation of pain
from peripheral nerve pain and to identify the pathway that might mediate the
peripheral process [24]. In few instances nerve blocks could also have a therapeutic
effect. Some of the nerve blocks that are used in orofacial pain disorders are aimed
to anesthetize the teeth (anterior, middle, and posterior superior alveolar nerve, infe-
rior alveolar nerve, and mental nerve) and infraorbital nerve.
Joint or intracapsular injections can be of therapeutic value and are indicated
when medications have to be released into the TMJ, usually corticosteroids or
sodium hyaluronate. For diagnostic purposes a nerve block of the auriculotemporal
nerve might help differentiate a joint source of pain from a muscular source [24].
28.4.16 Serologic Studies
Serologic examination is helpful to rule out rheumatologic conditions when there is

some suspicion of a connective tissue disease. Rheumatoid factor and antinuclear
antibodies (ANA) may provide helpful information when juvenile rheumatoid

arthritis or systemic lupus erythematous is suspected. An erythrocyte sedimentation
rate (sed rate) and/or C-reactive protein are nonspecific indicators of inflammation
and useful to diagnose temporal arteritis in patients complaining about a throbbing
aching pain in the temple area. Iron, ferritin, folate, and vitamin B 12 levels can
occasionally be useful in patients with burning mouth syndrome, due to the known
correlation between deficiencies in them and burning symptoms.
28.4.17 Temporomandibular Joint Imaging
Occasionally imaging is needed to establish an accurate diagnosis. Imaging is

indicated in trauma, acute changes in occlusion, limitation of mouth movement,
and crepitus and when systemic diseases, swelling, and infections are being con-
sidered. Imaging is also important if there is failure to respond conservative
treatment [29].
28.4.18 Plain Films
Mainly panoramic radiographs are used as a baseline imaging to rule out an odon-
togenic source of pain and trauma and to evaluate hard tissue structures of the
TMJ. A panorex provides a sectional view of the condyles and may reveal changes
in the bone surfaces [30] (Fig. 28.14). An open and closed TMJ series can be done
to evaluate the condylar translation and positioning. Other plain radiograph tech-
niques such as transcranial view, transpharyngeal view, and anterior posterior (AP)
view are available [24] but rarely necessary today.
28.4.19 Computed Tomography (CT)
CT allows the detailed examination of the bony structures of the TMJ on sagittal,
coronal, and axial views. CT is mainly indicated to determine the location and
extension of bone alterations: fractures, neoplasm, ankyloses, and degenerative
changes [31]. An open and closed sequence can also be performed (Fig. 28.15).
Fig. 28.14 Panoramic
reconstruction (Courtesy
Dr. M. Mupparapu)
Fig. 28.15 TMJ CBCT showing axial, sagittal, and coronal views (Courtesy Dr. M. Mupparapu)
Fig. 28.16 TMJ MRI

(Courtesy Dr. M. Mupparapu)
28.4.20 Magnetic Resonance Imaging (MRI)
MRI is a noninvasive (nonionizing radiation) technique based on the ability to cap-

ture the signaling from the hydrogen nuclei after a charge in a magnetic field [24].
MRI is used to evaluate the soft tissues of the TMJ, due to the great contrast resolu-
tion compared with other imaging techniques [32]. MRI is indicated to assess the
position and shape of the articular disc, the presence or absence of fluid within the
joint, and bony or synovial changes [30] (Fig. 28.16).
28.4.21 Behavioral and Psychological Assessment
As mentioned before, the pain experience is accompanied by an emotional compo-

nent that often modulates the pain perception. Pain tends to escalates if it is chronic.
When psychological factors (Axis II) predominate over somatic pain factors, thera-
peutic considerations are required [24]. Due to the known correlation between anxi-
ety, depression, and somatization levels with orofacial pain disorders, the Research
Diagnostic Criteria for TMD (RDC/TMD) included a questionnaire to assess the
psychologic component [33]. Many other methods to screen or assess the patient
psychologically are available and can be used depending on the clinician’s experi-
ence in interpreting the results.
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João N. A.

ISBN 978-3-319-51507-6 ISBN 978-3-319-51508-3 (eBook)

Library of Congress Control Number: 2017943711

© Springer International Publishing AG 2017

Printed on acid-free paper

This Springer imprint is published by Springer Nature

Part I Oral Cancer and Premalignant Lesions

Part II Oral Mucosal Diseases

Part III Oral Diseases of the Senses

Part IV Salivary Gland Dysfunctions

11 Salivary Hypofunction in Aging Adults �������������������������������������������������� 105

Part V Oral Parafunctions and Sleep Disorders

Part VI Temporomandibular Disorders and Occlusal Dysfunction

Part VII Orofacial Pain Disorders

Part VIII Headaches

Part IX Health Care Approaches in Orofacial and Widespread Pains

Part X A Comprehensive Approach to Orofacial Disorders

I. van der Waal, DDS, PhD

© Springer International Publishing AG 2017 3

• Because of the lack of prospective randomized trials, it is questionable

1.2 Clinical Presentation

• Oral leukoplakias are clinically classified into homogeneous and nonhomoge-

Fig. 1.5 Erythroplakia of

1.3 Etiology and Epidemiology

• Oral leukoplakias occur much more often in smokers than in non-smokers.

1.4 Pathophysiology and Mechanisms

1.5 Diagnosis and Diagnostic Criteria

• The diagnosis of oral leukoplakia is in most cases primarily based on clinical

• The pathologist report should include a statement on the absence or presence of

Fig. 1.7 Leukoplakia of

1.6 Rationale for Treatment

Treatment is directed at removal of symptoms, if any, but above all at prevention of

1.7 Treatment Options

• Spontaneous regression of oral leukoplakia is rare.

1.8 Treatment Goals and Sequencing of Care

In case of symptoms consider the taking of a biopsy

Good response No response Biopsy

No epithelial dysplasia Epithelial dysplasia Definable lesion;

Treatment, if feasible Treatment indicated

• Possible other etiologic factors should be eliminated, such as sharp edges of

7. Chainani-Wu N, Madden E, Cox D, Sroussi H, Epstein J, Silverman Jr S. Toluidine blue aids in

D.E. Peterson, DMD, PhD

© Springer International Publishing AG 2017 15

2.2 Clinical Presentation

Fig. 2.1 Early squamous

Fig. 2.3 Squamous cell

2.3 Etiology and Epidemiology

2.4 Pathophysiology and Mechanisms

• Tobacco use, with or without alcohol abuse

Factors possibly linked to oral SCC carcinogenesis include [3]:

• Deficiencies in antioxidant vitamins and nutrients

• Deficiency or excess of dietary proteins, fats, or carbohydrates

2.5 Diagnosis and Diagnostic Criteria

Adjunctive diagnostic aids [3] include:

Additional diagnostic strategies including imaging (computed tomography, mag-

2.6 Rationale for Treatment

Treatment rationale is directed to surgical removal, combined with cytotoxic ther-

• Tumor histopathologic diagnosis

2.7 Treatment Options

2.8 Treatment Goals and Sequencing of Care

G.D. Klasser, DMD (*)

© Springer International Publishing AG 2017 21

Table 3.1 Classification of Orofacial pain due to cancer

11 Salivary Hypofunction in Aging Adults �� 105

1.2 Clinical Presentation

1.3 Etiology and Epidemiology

1.4 Pathophysiology and Mechanisms

1.5 Diagnosis and Diagnostic Criteria

1.6 Rationale for Treatment

1.7 Treatment Options

1.8 Treatment Goals and Sequencing of Care

2.2 Clinical Presentation

2.3 Etiology and Epidemiology

2.4 Pathophysiology and Mechanisms

2.5 Diagnosis and Diagnostic Criteria

2.6 Rationale for Treatment

2.7 Treatment Options

2.8 Treatment Goals and Sequencing of Care

3.2 Clinical Presentation and Diagnostic Subtypes

3.3 Etiology and Epidemiology

3.4 athophysiology and Diagnosis: Importance

3.4.1 Mechanisms of Orofacial Pain from Cancer

3.4.2 Mechanisms Due to Nonsurgical Management of Cancer

3.4.3 Mechanisms Due to Surgical Procedures for Cancer

3.4.5 Orofacial Pain Due to Other Etiologies

3.5 Rationale for Treatment

3.6 Treatment Options, Goals, and Sequence of Care

4.2 Clinical Presentation

4.3 Etiology and Epidemiology

4.6 Rationale for Treatment

4.7 Treatment Options

4.8 Treatment Goals

5.2 Clinical Presentation

5.2.1 Common Symptomatology

5.3 Etiology and Epidemiology

5.3.1 Etiological Considerations According to Each Condition

5.4 Pathophysiology and Mechanisms

5.5 Diagnosis and Diagnostic Criteria

5.5.1 Clinical Diagnostic Criteria for OVED

5.5.2 Laboratory Diagnostic Criteria for OVED

5.6.1 Rational for Treatment

5.6.2 Treatment Options

5.6.3 Home Care